Download nuclear hormone receptors enable macrophages and dendritic cells

Physiol Rev 92: 739 –789, 2012
doi:10.1152/physrev.00004.2011
NUCLEAR HORMONE RECEPTORS ENABLE
MACROPHAGES AND DENDRITIC CELLS TO SENSE
THEIR LIPID ENVIRONMENT AND SHAPE THEIR
IMMUNE RESPONSE
Laszlo Nagy, Attila Szanto, Istvan Szatmari, and Lajos Széles
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, and Apoptosis
and Genomics Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and
Health Science Center, Debrecen, Hungary
L
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
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XI.
INTRODUCTION
MACROPHAGES ARE IMMUNE...
THE MAIN FUNCTIONS FOR DENDRITIC...
RXR AND ITS PARTNERS: RAR,...
THE BIOLOGY OF RAR AND RXR...
THE BIOLOGY OF LXR IN...
THE BIOLOGY OF PPAR␥...
THE BIOLOGY OF VDR IN...
COMPLEXITY OF GENE REGULATION...
LIGAND PRODUCTION BY DENDRITIC...
CONCLUSIONS AND PERSPECTIVES
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I. INTRODUCTION
The fate of cells is largely determined by the quantitative
and qualitative gene expression changes, which are taking place as the result of alterations in endo- and exoge-
nous signaling. It is becoming increasingly clear that the
major direct initiators and regulators of such changes are
transcription factors, which can bring about the changes
necessary to alter cellular differentiation and cell fates.
Probably the most well-documented cases of cell fate
determination processes are examples of cellular differentiation. During these processes, a coordinated set of
signals govern the differentiation and cell type specification of stem and/or progenitor cells into diverse directions.
Conceptually, a fairly well understood system is the differentiation of bone marrow-derived myeloid progenitor
cells of the immune system such as macrophages or dendritic cells (DCs) (151, 169) amongst others. These cell
types are particularly intriguing because they are not just
key components of the immune system, but are also pres-
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Nagy L, Szanto A, Szatmari I, Széles L. Nuclear Hormone Receptors Enable Macrophages and Dendritic Cells to Sense Their Lipid Environment and Shape Their Immune
Response. Physiol Rev 92: 739 –789, 2012; doi:10.1152/physrev.00004.2011.—A
key issue in the immune system is to generate specific cell types, often with opposing
activities. The mechanisms of differentiation and subtype specification of immune cells
such as macrophages and dendritic cells are critical to understand the regulatory principles and
logic of the immune system. In addition to cytokines and pathogens, it is increasingly appreciated
that lipid signaling also has a key role in differentiation and subtype specification. In this review we
explore how intracellular lipid signaling via a set of transcription factors regulates cellular differentiation,
subtype specification, and immune as well as metabolic homeostasis. We introduce macrophages and
dendritic cells and then we focus on a group of transcription factors, nuclear receptors, which regulate
gene expression upon receiving lipid signals. The receptors we cover are the ones with a recognized
physiological function in these cell types and ones which heterodimerize with the retinoid X receptor.
These are as follows: the receptor for a metabolite of vitamin A, retinoic acid: retinoic acid receptor
(RAR), the vitamin D receptor (VDR), the fatty acid receptor: peroxisome proliferator-activated receptor
␥ (PPAR␥), the oxysterol receptor liver X receptor (LXR), and their obligate heterodimeric partner, the
retinoid X receptor (RXR). We discuss how they can get activated and how ligand is generated and
eliminated in these cell types. We also explore how activation of a particular target gene contributes to
biological functions and how the regulation of individual target genes adds up to the coordination of gene
networks. It appears that RXR heterodimeric nuclear receptors provide these cells with a coordinated
and interrelated network of transcriptional regulators for interpreting the lipid milieu and the metabolic
changes to bring about gene expression changes leading to subtype and functional specification. We
also show that these networks are implicated in various immune diseases and are amenable to
therapeutic exploitation.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
to mediate lipid signaling at the level of gene expression
(318). Due to the fact that these transcription factors are
intimately linked to lipid metabolism, they represent an
important crossroad between lipid metabolism and immune
function (161, 211, 503). In this review, we focus on a
selected group of nuclear hormone receptors, RXR heterodimers (318) (TABLE 1) and evaluate the available evidence on how activation of these receptors can modulate
cell fate decisions in macrophages and DCs. How these
pathways are interacting with cytokine signaling and how
these might be linked to disease states such as atherosclerosis, inflammation, and host response to pathogens will also
be discussed.
As a general principle, the differentiation and specification of these cells are regulated by endogenous and exogenous stimuli, including cytokines and TLR ligands, respectively (151, 168, 169) (FIGURE 1). However, it is
increasingly appreciated that changes in the lipid environment also contribute to cell type differentiation and
specification mainly by alterations of transcriptional responses.
II. MACROPHAGES ARE IMMUNE CELLS
WITH DIVERSE BIOLOGICAL
FUNCTIONS
In multicellular organisms, a distinct set of transcription
factors, the superfamily of nuclear receptors, have evolved
A. Macrophages Are More Than Just “Big
Eaters”
It was more than 100 years ago when Elie Metchnikoff
discovered macrophages (␮␣␹␳␱␵ ⫽ large and ␾␣␥⑀␫␯ ⫽
eat) and assigned phagocytosis as their major function
FIGURE 1. The impact of endogenous and exogenous stimuli including nuclear receptor ligands on macrophages and dendritic cells. Schematic representation of the principles of macrophage/dendritic cell differentiation from precursors. Host-derived and pathogen-derived stimuli trigger and regulate the activation/maturation of the precursor cells (monocytes, non-activated macrophages, and immature dendritic cells). The way
of activation/maturation of the effector cells (activated macrophages and mature dendritic cells) depends on
the input signals and the signal integration. Some stimuli, e.g., Toll-like receptor (TLR) ligands and proinflammatory cytokines can initiate subtype specification. Other stimuli, e.g., nuclear receptor ligands, typically do not
trigger these processes, but they have the capacity to modify or antagonize the activation/maturation
programs. For simplicity, this schematic representation does not illustrate many aspects of the influence of
stimuli on macrophages and dendritic cells. For example, many nuclear receptor ligands are more efficient if
they act before inflammatory stimuli (“reprogramming”). Subtype specification itself is also more complex than
it is represented here, e.g., not all dendritic cell subtypes have to undergo maturation to fulfill their function.
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ent in all tissues and many compartments of the body
representing a wide array of subtype specification pathways such as classically and alternatively activated macrophages, different tissue macrophages, Kupffer cells, alveolar macrophages, microglia, or among DCs plasmacytoid and conventional DCs, such as Langerhans cells
(151, 169). Importantly, these cell types are often exposed to large amounts of lipids, including pathogen- and
host-derived lipoproteins or lipids of apoptotic cells;
therefore, they represent a well-suited model to study and
understand the regulatory principles and logic of the integration of lipid and inflammatory signaling with gene
expression at the cellular level (503).
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Most common/canonical
responsive elements
Transcriptional unit
Examples of synthetic
ligands
Proposed/prototypic
natural ligands
Main physiological
functions
Differentiation
Binding partner for other
nuclear receptors,
differentiation
9-cis retinoic acid,
doxosahexonoic acid,
phytanic acid
Rexinoids, e.g.,
LG100268
Many heterodimers and
probably homodimer
According to the partner
preference, DR-1 for
homodimer
RAR␤ (NR1B2 ):
ubiquitously expressed
RAR␥ (NR1B3 ):
ubiquitously expressed
RXR␤ (NR2B2):
ubiquitously expressed
RXR␥ (NR2B3):
ubiquitously expressed
DR-5
DR-4
Permissive heterodimer
T0901317
TTNPB
Conditional heterodimer
GW3965
Oxysterols
Cholesterol metabolism
LXR␣ (NR1H3): liver, adipose
tissue, intestine, lung,
kidney, adrenal glands, and
macrophages
LXR␤ (NR1H2): ubiquitously
expressed
Liver X Receptors (LXRs)
AM580
9-cis retinoic acid, all-trans
retinoic acid
RAR␣ (NR1B1):
ubiquitously expressed
RXR␣ (NR2B1):
ubiquitously expressed
Retinoic Acid Receptors
(RARs)
Nonpermissive heterodimer
␥: Thiazolidinediones, NPC15199,
GW1929, GW7845
␦: GW501516,GW0742
Dual agonists
Permissive heterodimer
DR-3
MC903 (calcipotriol)
␣: WY14643, GW7647, AM3102
DR-1
1␣,25-Dihydroxyvitamin D3
Calcium metabolism and bone
homeostasis
VDR (NR1I1): highly expressed in the
gastrointestinal system, with
moderate levels in the kidney,
thyroid, bone, and skin
Vitamin D Receptor (VDR)
Polyunsaturated and oxidized fatty
acids
PPAR␤ (NR1C2), also called PPAR␦:
ubiquitously expressed
PPAR␥ (NR1C3): white adipose
tissue, macrophages, and
dendritic cells
Lipid metabolism
PPAR␣ (NR1C1): expressed mainly
in in metabolic tissues (brown
adipose tissue, liver, and kidney)
Peroxisome Proliferator Activated
Receptors (PPARs)
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Isotypes and tissue
distribution
Retinoid X Receptors
(RXRs)
Table 1. Summary of nuclear receptor localization and activity
NAGY ET AL.
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NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
(253). Today macrophages represent a very heterogeneous and highly specialized cell population (151). They
are involved in many steps of innate and adaptive immune responses, being essential players in antigen presentation, wound healing, elimination of bacteria, removal of necrotic cellular debris, and secretion of cytokines. Moreover, several lines of evidence support a
central role for macrophage-mediated inflammation in
the pathogenesis of metabolic diseases, most importantly
atherosclerosis, but also in diabetes and metabolic syndrome (163, 392).
B. Development of
Monocytes/Macrophages
CD34⫹ stem cells can give rise to every cell type in the
blood. Traditionally, it was believed that monocytes develop from common myeloid progenitors of granulocytes
and monocytes termed colony-forming units (CFUs); therefore, the generation of monocytes is part of the general
differentiation process of myeloid cells, termed myelopoiesis. Differentiation starts from stem cells with the formation
of granulocyte, erythrocyte, monocyte, and megakaryocyte
colony forming unit (CFU-GEMM), which give rise to granulocyte, macrophage colony-forming unit (CFU-GM) upon
the effect of granulocyte-macrophage colony stimulating
factor (GM-CSF). Subsequently, macrophage colony-forming unit (CFU-M or CMP ⫽ common myeloid precursor) is
induced by macrophage colony-stimulating factor (MCSF). This develops into monoblast and later promonocyte
to finally give rise to monocytes (144, 145). However, the
relationship between the origin of monocytes and dendritic
cells remains controversial. The existence of a common precursor monocyte DC precursor (MDP) has been shown, but
its relationship to common DC precursor (CDP) is still unresolved (see also sect. IIIB) (139).
There are distinct types of monocytes in the blood: 1) classical monocytes are characterized as CD14⫹⫹CD16⫺ while
2) nonclassical monocytes show low CD14 and high CD16
cell surface expression (CD14⫹CD16⫹⫹) (595). Recent nomenclature distinguishes a third category as well termed intermedier monocytes (CD14⫹⫹ CD16⫹) (569).
CD14⫹CD16⫹⫹ monocytes express CC-chemokine receptor 5 (CCR5), whereas CD14⫹⫹CD16⫺ monocytes express
CCR2 (557). This pattern is characteristic for human
monocytes. However, murine monocytes are also heteroge-
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Monocytes can migrate through the endothelium of blood
vessels upon various stimuli. During this extravasation they
undergo several changes to become macrophages or DCs.
Monocytes/macrophages can be characterized by the high
level of CD14, CD11b, CD36, CD68 and F4/80 in mice or
by epidermal growth factor-like module containing, mucinlike, hormone receptor-like 1, also known as EMR1, lysozyme M, macrophage antigen-1/3, and M-CSF receptor.
The major function of monocytes is related to the immune
system: once they differentiate into macrophages and inflammatory DCs, they are either attracted to inflammatory
sites or survey the tissues for foreign/accumulated molecules and pathogens to engulf. In response to inflammatory
stimuli, monocytes are rapidly recruited to the sites of inflammation where they are involved not only in the killing/
elimination of such particles but evoke specific signaling
processes to activate further immune mechanisms. Macrophages are also capable of activating adaptive immune responses, whilst DCs are considered to be more efficient in
this. Another important role for macrophages stems from
their potency on metabolizing lipid molecules. Probably as
part of its original protective role against foreign substances, macrophages are also capable of recognizing lipid
molecules when accumulating within the tissues. This process linked macrophages to metabolism, and roles have
been assigned for them in the process of atherosclerosis and
lipid storage diseases. Recently, by studying the crosstalk of
immune system and lipid metabolism, macrophages have
been involved in the process of obesity and insulin resistance as particular cell types regulating lipid metabolism
and inflammation in adipose tissue (392; for details, see
below).
The differentiation of myeloid cells is principally regulated
by cytokines and orchestrated via cooperative gene regulation by transcription factors. The most important players
are PU.1, CCAAT/enhancer binding proteins (C/EBPs), and
AP-1. For a detailed overview of transcriptional control of
granulocyte and monocyte development, we refer to other
reviews (144, 145). Briefly, at early stages of hematopoiesis,
PU.1 directs stem cells to the lymphoid-myeloid lineage by
inhibiting megakaryocyte-erythroid differentiation via interacting with GATA-binding protein (227, 330, 465). In
the next step C/EBP␣ inhibits lymphoid, whilst induces
granulocyte-monocyte development (589, 590). PU.1 again
induces monocytic commitment (107, 278). PU.1 itself is
induced by C/EBP␣ (550) and activated by c-Jun (37).
C/EBP␣ together with c-Jun or c-Fos favors monocytic
development (294, 308, 496), which is further assisted by
protein kinase C (PKC), Egr-1, Egr-2, VDR, MafB/c, and
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Monocytes constitute ⬃3– 8% of circulating leukocytes
and are produced in the bone marrow from hematopoietic stem cell progenitors. After differentiation they are
released into the circulation from where they move into
tissues usually within 1–3 days. According to a recent
report, there is a reservoir for monocytes in the spleen
where they form clusters in the cords of the subcapsular
red pulp (495).
neous. CCR2⫹CX3CR1low cells correspond to the human
CD14⫹⫹CD16⫺ inflammatory monocytes, while resident
monocytes are CCR2⫺CX3CR1hi, corresponding to the human CD14⫹CD16⫹⫹ cells (152, 169).
NAGY ET AL.
interferon regulatory factor 8, while RAR and C/EBP⑀
direct granulopoiesis. Phorbol esters are widely used as
inducers of monocytic maturation of myeloid cell lines.
They activate PKC-␣, which in turn activates c-Jun kinase 2, that will activate c-Jun and induce monocytic
maturation (413).
C. Macrophage Activation and Function in
Innate Immunity
As a result of their studies on mannose receptor, Gordon
and colleagues (484) discovered another class of activated
macrophages, which they termed alternatively activated
macrophages (or M2 on FIGURE 4C). Alternative macrophages, in contrast to the classically activated cells, express
high levels of mannose receptor and exert an almost opposite immunophenotype. They cannot produce nitrogenmonoxide and radicals required for killing, they inhibit T
However, a growing body of evidence suggests that the
group of nonclassically activated macrophages itself is
heterogeneous and exhibits significant differences in their
biochemistry and physiology. Therefore, some authors
suggest that, based on their functions, macrophages
should be classified into three major groups: classically
activated macrophages (playing important roles in host
defence), wound healing macrophages, and regulatory
macrophages. In addition to these categories, there are
macrophages that share characteristics of two groups,
e.g., tumor-associated macrophages, which have many
characteristics of regulatory macrophages but also share
some characteristics of wound-healing macrophages
(353, 354).
D. Antigen Presentation by Macrophages:
Induction of Acquired Immunity
Macrophages phagocytose self-proteins and cells during
normal tissue repair and aging. These self-proteins do not
activate T cells, because in the absence of infection, macrophages in general express low levels of major histocompatibility complex (MHC)-II and costimulatory molecules.
However, lipopolysaccharide (LPS) and various cytokines
stimulate macrophages to upregulate MHC-II and B7
(CD80 and CD86 together) molecules, providing these cells
with strong antigen presentation properties. This is complemented by their ability to uptake and process antigens. In
addition, macrophage activation results in upregulation of
cytokines such as IL-1, IL-6, IL-8, IL-12, and TNF (324,
529). With these capacities, macrophages are able to activate memory and effector T cells, but not naive T cells.
Interestingly, a subset of specialized macrophages (subcapsular sinus macrophages) contribute to early delivery of
antigens to B cell follicules at the subcapsular sinus of
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Macrophages are central players of innate immunity not
only because they eliminate pathogens, cellular debris, and
senescent and dying cells, but they also produce a range of
secretory products, which affect the migration and activity
of other immune cells. Macrophages are inherently heterogeneous, as they need to respond to a variety of signals in
very different tissue contexts. One level of heterogeneity
originates from the localization of the resident macrophages. There are specialized macrophages with more or
less different functions, like Kupffer cells in the liver, microglia in the central nervous system, osteoclasts in the bone,
alveolar macrophages in the lung, perivascular macrophages, and Hofbauer cells in the placenta, etc. (168, 169)
(FIGURE 2). Another level of heterogeneity is initiated by
environmental signals, most importantly cytokines and
pathogen-derived molecules. Initially, activated macrophages were defined as cytokine-producing cells that are
able to kill pathogens (108). However, the changing inflammatory milieu could result in distinct activation of cells
leading to subpopulations with specialized functions. The
distinct functions require highly specialized cells, which are
differentiated upon cytokines and microbial products
(312). Pro-inflammatory molecules like interferon-gamma
(IFN-␥), tumor necrosis factor (TNF), and activators of
pattern recognition molecules like Toll-like receptors
(TLRs) induce the so-called classical activation of macrophages (classically activated macrophages, or M1 on
FIGURE 4C). Consequently, macrophages migrate to the
sites of inflammation to engulf and degrade pathogens by
producing nitrogen-monoxide and radicals. They also secrete proinflammatory molecules such as TNF, interleukin
(IL)-1, IL-6, and MCP-1 to sustain the inflammatory reaction. This classical pathway of IFN-␥-dependent macrophages activation provokes Th1-type responses and serves
as an efficient arm of innate immunity directed against intracellular pathogens, like Listeria monocytogenes or Mycobacterium tuberculosis (165, 353).
cell proliferation (459), and they provoke immunotolerance
or Th2 immune responses (104). They can also produce
anti-inflammatory molecules such as transforming growth
factor (TGF)-␤, IL-10, or IL-1 receptor antagonist (138,
165, 459) and inhibit the secretion of pro-inflammatory
molecules such as IL-1, TNF, IL-6, IL-12, and macrophage
inhibitory protein (MIP)-1␣ (50, 86, 482). Alternatively
activated macrophages can be characterized by high levels
of mannose receptor (484), CD23 (34), alternative macrophage activation-associated chemokine 1 (AMAC-1 or
CCL18) (264), arginase-1 (361), FIZZ1, and YM1, (421).
The alternative activation of macrophages is induced by
Th2 cytokines IL-4 and IL-13 and results in a distinct macrophage subpopulation with roles in humoral immunity
and resolution such as repair, wound healing, angiogenesis,
tissue repair, and extracellular matrix deposition (164, 168,
173, 264, 265, 353). Under in vivo conditions, alternatively
activated macrophages are found at border surfaces in the
body such as lung, placenta, and perivascular space (75,
136, 264, 300, 358).
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NAGY ET AL.
lymph nodes (69, 411) by collecting and distributing native
antigens. It should be mentioned that macrophages, in particular, alveolar macrophages and tumor-associated macrophages, have been linked to suppression of T cells as well
(363, 577). Clearly, macrophage subtype specification has
an important role in determining the direction of the immune response, and thus macrophages are important amplifiers of the adaptive immune response.
E. Macrophages in Metabolic Processes
Vessels are covered by a single cell layer, the endothelium,
that serves as a barrier between the circulating blood and
subendothelial tissues. Molecules and cells have to migrate
through this layer to reach their destination in a regulated
fashion. Preferred sites where atherosclerotic lesion starts to
develop are places with vulnerable endothelium, i.e., where
the cell layer is injured or gets injured easier than at other
sites. A disturbance in the laminar flow of blood is, for
example, one such factor that increases endothelial vulnerability. Independently of the cause, endothelial dysfunction
Macrophages are considered to be the first cellular components in lesion formation. They take up lipid particles
through specialized cell surface proteins termed scavenger
receptors (SRs), such as SR-A and CD36. Importantly, these
scavenger receptors are not subjected to downregulation via
a negative-feedback mechanism such as in the case of LDL
receptor. Consequently, the more lipid molecules that are
present, the higher the lipid concentration in the cells will be
leading to the appearance of the characteristic macrophage
subtype, the lipid-loaded foam cells. These cells can be identified already in the fatty streaks. Macrophages not only
take up lipid particles from the environment, but they metabolize them and eliminate lipids through their ATP-binding cassette transporters such as ABCA1 and ABCG1 towards high-density lipoprotein (HDL). If there is an imbalance between the amount of lipids taken up and the
metabolizing/effluxing capacity of the macrophages, they
start accumulating lipids resulting in increased cell death
and sustained chronic inflammation (163, 190, 298). As a
consequence of the chronic inflammation, smooth muscle
cells migrate from the tunica media and go through a fibroblast-like transformation resulting in proliferation and production of extracellular matrix elements. This leads to the
formation of the late, fibrous atherosclerotic plaques. If
calcification (sclerosis) occurs, the artery wall becomes rigid
and fragile. Finally, the originally stable lesion may change
FIGURE 2. Development and in vitro models of macrophages and dendritic cells (DC). A: development and the most important subtypes of
macrophages and DC. Macrophages and DC can be found in many tissues, and they can play different functions. Conventional DC, plasmacytoid
DC, and monocytes share a common progenitor, the macrophage and DC precursor (MDP). However, recent data indicate that some
macrophage and DC subtypes, e.g., microglial cells and Langerhans cells, are not necessarily derived from this common bone marrow
progenitor. B: in the two most common in vitro models, macrophages and DC are differentiated from murine bone marrow cells and human
monocytes in the presence of growth factors and cytokines. Activated macrophages and mature DCs usually are obtained by using Toll-like
receptor (TLR) ligands and/or various cytokines.
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There is a rich array of interactions between inflammation
and metabolism. Pathogens and inflammation itself could
disturb metabolic processes, and vice versa, chronic metabolic diseases could lead to abnormal immune reactions. In
some cases, it is hard to deconvolute what is cause and what
is consequence. Metabolic syndrome, a constellation of
metabolic abnormalities including insulin resistance, hypertension, dyslipidemia, and central obesity, is very often coupled to atherosclerosis, a progressive, degenerative disease
of blood vessels. Atherosclerosis is a good example of the
intersection of metabolic and immune processes, especially
if one considers the pivotal role of macrophages. The progression of the atherosclerotic lesion starts after birth, and
generally, the first clinical manifestations occur in the sixth
decade of life. Complications of atherosclerosis such as
ischemic heart disease, myocardial infarction, and stroke
make atherosclerosis responsible for most of the deaths in
western societies. The first sign of lesion formation in the
vessel wall is the lipid/cholesterol accumulation observed by
the appearance of fatty streaks within the subintimal tissues
(175) (FIGURE 6). Cholesterol accumulation is driven by
pathogenic interaction between circulating lipoproteins, hemodynamic factors, endothelial cells, vascular smooth muscle cells, macrophages, and T lymphocytes and results from
the abnormal handling of lipids by macrophages (163, 311,
475).
results in the accumulation of low-density lipoprotein
(LDL) in the subendothelial matrix (311). It is not clear how
LDL gets modified, but this leads to the appearance of minimally oxidized/modified LDL (mmLDL) and subsequently
fully oxidized LDL (oxLDL) containing multiple oxidized
lipid molecules (163). Oxidatively modified lipoproteins
and lipids can activate both endothelial cells and monocytes/macrophages leading to the migration of monocytes
into the subendothelial space (420). Here, macrophages
start taking up and clearing up the accumulating lipid particles. However, this might be incomplete and/or the continuous supply from the circulation overloads the lipid handling capacity of the macrophages leading to chronic inflammation with further accumulation of lipids and
involvement of multiple cell types, such as endothelial cells,
additional macrophages, granulocytes, lymphocytes, fibroblasts, and smooth muscle cells from the media of the vessel.
The release of inflammatory mediators and chemoattractants by these cells evokes a characteristic inflammatory
response around lipid accumulation by attracting additional cells to the lesion (377, 420, 485).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
into an unstable vulnerable plaque that can easily rupture
the endothelium leading to the formation of thrombus and
intravascular coagulation.
Nuclear receptors, most importantly PPAR␥ and LXRs,
have been implicated in the regulation of lipid metabolism in several cell types contributing to lesion initiation,
development, and progression. These include macrophages, fibroblasts, T lymphocytes, smooth muscle cells,
and endothelial cells. We will detail the role and contribution of PPAR␥ and LXR in the formation of atherosclerotic lesions (41, 73, 161, 211, 501, 523) in sections
VI and VII.
According to some reports, more than 40% of the total
adipose tissue cell content from obese rodents and humans
can be macrophages, while in lean counterparts this value is
⬃10% (559). The suggestion is that adipose tissue macrophages or ATMs are the major sources of cytokines, which
can function as paracrine and/or endocrine mediators of
inflammation leading to decreased insulin sensitivity. It is
believed that activation of macrophages leads to the production and release of chemokines and cytokines such as
IL-1␤, TNF-␣ and IL-6. This leads to the activation of Jun
NH2-terminal kinase (JNK) (29, 202), inhibitor of ␬B kinase ␤ (IKK␤), and other kinases (224). The insulin-resistant state is characterized by increased JNK and IKK␤ levels
in adipose tissue and skeletal muscle. This in turn leads to
activation of AP-1 and NF-␬B and the subsequent transcriptional activation of inflammatory genes. Insulin receptor
substrate also gets phosphorylated, leading to cellular insulin resistance. Nuclear receptors, most prominently PPAR␥,
have been linked to these macrophages and to disease progression as it will be discussed in section VII.
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A. Antigen Presentation by Dendritic Cell Is
a Key Step in Engaging the Adaptive
Immune Response
Traditionally, macrophages and B cells were thought to be
the only cell types able to present antigens to T cells and
thus elicit immune response. However, Steinman and Cohn
(487) showed that another kind of antigen-presenting cell
types, DCs, are indispensable for the initiation of the adaptive immune response (28). DCs can be considered as effector cells with the potential to interact with lymphocytes and
regulate their function (430). DCs also play an important
role in innate immune responses, e.g., plasmacytoid DCs
produce type I IFNs in response to viral infection, while
TNF-␣/inducible nitric oxide synthase (iNOS)-producing
DCs mediate defense against bacterial infection (466, 486).
Moreover, in addition to eliciting immune response, DCs
could also provoke immunological tolerance by inducing
deletion or anergy; thus DCs contribute to limiting autoimmunity (96).
DCs can be found in lymphoid organs, in the blood, at body
surfaces (e.g., the skin, pharynx, upper esophagus, vagina,
and anus), and at mucosal surfaces such as the respiratory
and gastrointestinal system (486) (FIGURE 2). Importantly,
DCs can be generated in vitro from precursors found in the
bone marrow, spleen, or blood (monocyte-derived DC),
allowing studies using large amount of cells (222, 452, 568)
(FIGURE 2). Similarly to macrophages, DCs form a heterogeneous cell population, and DC subsets differ in function,
location, migratory pathways, and activation status. Remarkably, we do not have any good phenotypic markers
specific to DCs, nor any functional criteria; therefore, the
clear distinction of DCs from macrophages is still problematic (151, 220).
Early studies, using mainly Langerhans cells (DCs in the
epidermis), demonstrated that DCs exist in two states:
“off” (immature) and “on” (mature) (430). The paradigmatic Langerhans cell life cycle and migratory pathways
were modeled based on studies carried out in the 1980s
(246, 430, 540, 567). According to this model, migratory
DCs such as Langerhans cells, work at the interface of peripheral tissues. These cells are sentinels of the immune
system, and they sense and translate environmental cues by
sampling and processing extracellular and intracellular antigens. DCs uptake antigen by various mechanisms (383,
456) and migrate to lymph nodes, where they present antigens and stimulate T cells. The pathogen-derived signals,
pro-inflammatory cytokines, and danger signals all integrated by DCs and define the immune response. These ac-
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Another metabolic condition in which the involvement of
macrophages has been highlighted in recent years is metabolic syndrome itself (for a review, see Ref. 392). It is an
emerging concept that inflammation appears to be a component of obesity-associated insulin resistance. Several
lines of evidence including genetic as well as pharmacological inhibition of pathways contributing to inflammatory responses were found to protect against diet-induced
insulin resistance. In addition, it has been shown that
chronic activation of intracellular pro-inflammatory
pathways in target tissues of insulin leads to obesityrelated insulin resistance. Another relevant feature of the
disease condition is that macrophages are present in adipose tissue of obese individuals more than in lean ones.
Moreover, these cells appear to be the major sources of
inflammatory cytokines linked to insulin resistance such
as TNF-␣ (213, 460). Since it has been suggested that
adipose tissue from obese mice and humans are infiltrated with increasing number of macrophages (560,
571), it represents a major new paradigm potentially explaining the disease process.
III. THE MAIN FUNCTIONS FOR
DENDRITIC CELLS ARE ANTIGEN
PRESENTATION AND LYMPHOCYTE
ACTIVATION
NAGY ET AL.
tivating stimuli lead to the maturation of DCs and promote the
transition from an “antigen-sampling mode” to the “antigenpresenting mode” (430). Mature DCs deliver three types of
signals that are thought to be essential to initiate T-cell activation and determine the fate of naive T cells: antigen presentation (signal 1), costimulation (signal 2), and polarizing cytokines (signal 3) (247, 430).
The “Langerhans cell paradigm” has been a guiding principle in DC research (246, 430, 540, 567). However, it is clear
now that this model does not describe the function and life
cycle of several DC subsets. Three examples are given here
to illustrate the functional heterogeneity of DCs and the
differences from the original paradigm.
Second, DCs in secondary lymphoid tissues are not necessarily mature and not derived from cells previously resident
in peripheral tissues. Instead, many DCs in the spleen and
lymph nodes, especially in the steady state, are immature
and derived from blood-born progenitors (430, 540, 541,
567).
Third, DCs that express maturation markers are not always
immunogenic (the maturation concept is reviewed in details
in Ref. 430). Tolerogenic DCs are known to express substantial level of costimulatory molecules, and other maturation markers and certain environmental signals seem to
mature DCs into a tolerogenic mode.
B. Development and Origin of Dendritic Cells
Several DC subsets have been identified in both mice and
humans. These subsets are distinguished by marker expression, function, location in the body, and whether they are
generated in the steady state or during inflammation. Two
classes of DCs are present in the steady-state plasmacytoid
DCs and conventional DCs (FIGURE 2). Conventional DCs
can be further subclassified into migratory and lymphoidresident DCs. The precursor-progeny relationship of monocytes, macrophage, and DCs has been debated ever since the
discovery of DCs. There is also a significant difference between mouse and human DC subtypes, which must be taken
into consideration. Recent data indicated that both the plasmacytoid and the conventional lymphoid resident DCs derived from a common bone marrow progenitor. A CDP
(common DC precursor) was identified from bone marrow
that efficiently generated in vitro and in vivo plasmacytoid
and conventional DCs but not other cell lineages (372,
393). However, other researchers described that conven-
Moreover, it was demonstrated that at least a few subsets of
tissue resident DCs (inflammatory DCs) derived from
monocytes in vivo (152, 423). In addition human blood
monocytes are a commonly used precursors for ex vivo
generation of DC (monocyte-derived DC) (452).
Consistent with the common origin of macrophages and
DCs, several well-established transcription factors, which
were considered as a macrophage specific regulator, are also
important for DC development. For example, PU.1 transcription factor is required for myeloid DC development
(18, 179). Together these results suggested that probably a
similar set of transcription factors and signaling pathways
shapes the differentiation and function of DCs and macrophages.
The molecular details of the regulation of DC differentiation are still poorly characterized, although it was described that several cytokines and transcription factors
are necessary for DC development (570, 588). Flt3 ligand
is critical for the development of both conventional and
plasmacytoid DC differentiation; in contrast, GM-CSF
promotes only conventional DC development (570). In
addition, in humans, treatment with IL-4 and GM-CSF
cytokine is used for the ex vivo generation of monocytederived DCs (452). Much less is known about the transcriptional regulation of DC development, and only a few
putative “master” transcription factors have been identified so far (588).
Differentiation, lineage development, and also subtype
specification is known to be controlled by various cytokines
in the case of both macrophages and DCs. However, this
process is very much influenced by the extra- and intracellular lipid milieu (FIGURE 1). In the rest of this review, we
will summarize what is known about the contribution of
lipid-activated transcription factors, nuclear hormone receptors to these processes. Due to the large amount of data
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First, recent studies suggest that Langerhans cells are dispensable for T cell priming, and in vivo mouse Langerhans
cells appear to suppress the immune responses (151, 246,
259). These data are paradoxical considering that Langerhans cells are featured in many textbooks as prototypical
DCs.
tional DCs, monocytes (139), and even plasmacytoid DCs
(24) share a common progenitor, the MDP (macrophage
and DC precursor), suggesting that these cells have a common origin. The ontogenetic relation between MDP and
CDP is controversial. These progenitors probably represent
different stages of differentiation along the same pathway.
Indeed, a recent report suggested that MDPs produced
monocytes and CDPs, and CDPs are further restricted to
generate conventional DC precursors (pre-cDCs) and plasmacytoid DCs (301). Plasmacytoid DCs are profoundly different from conventional DCs. These cells live longer and
harbor characteristic immunoglobulin rearrangements.
They can be found in bone marrow, in the blood, and on the
periphery and are specialized to respond to viral infection
by producing massive amounts of IFN-␥. Plasmacytoid DCs
are also involved in antigen presentation and induction of
tolerance.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
available, we will restrict our review to receptors heterodimerizing with the RXR.
IV. RXR AND ITS PARTNERS: RAR, LXR,
PPAR, AND VDR
Although many other nuclear receptors [e.g., glucocorticoid receptor (GR) and estrogen receptor (ER)] are also
expressed and have documented immunomodulatory
role in macrophages and DCs, in this review we will focus
on RXR and its partners: RAR, LXR, PPAR␥, and VDR
(TABLE 1). We will not cover the potential role of other
RXR partners, e.g., Nurr1, PXR, CAR, and PPAR␦/␤,
because they are not expressed in these cells or have not
been investigated in sufficient details. In this section we
cover the general features (e.g., receptor isotypes, ligands, knockout phenotypes, and general functions) of
RXR and its partners, RAR, LXR, PPAR and VDR, while
in subsequent sections we review the specific roles for
these receptors in macrophages and DCs. Finally, we will
748
A. Retinoic Acid Receptors (RARs and
RXRs) Are Activated by Vitamin A
Derivatives
Vitamin A and its derivatives, retinoids, have profound
effects in development, differentiation, homeostasis, and
various aspects of metabolism. The discovery of retinoid
receptors substantially contributed to the understanding
of how these small, lipophilic molecules, most importantly retinoic acid (RA), work as a morphogenic hormone and exert their pleiotropic effects (159, 307, 336,
410). There are two families of retinoid receptors, RARs
and RXRs, that are capable of recognizing retinoids specifically and exert their biological effects by regulating
gene expression (112). Both families contain three isotypes: ␣, ␤, and ␥ encoded by separate genes and giving
rise to numerous alternatively spliced variants (60, 74,
249, 306, 317–319, 584).
RARs can be activated by all-trans-retinoic acid (ATRA)
and 9-cis-retinoic acid (9-cis RA), while RXRs can be activated only by 9-cis RA (200, 292). There are natural and
synthetic compounds with at least some selectivity for RXR
(33, 49, 283, 292) termed rexinoids (359).
RARs have been implicated in embryonic (336), skeletal,
(307), and myeloid development (248, 250); in wound healing; in keratinization (172); and also in the developing nervous system (491). RAR␣, RAR␤, and RAR␥ null mice are
viable. They display some aspects of the fetal (and postnatal) vitamin A deficiency (VAD) syndromes (566). For a
detailed overview, we refer the reader to a recent review
(323).
RXR has a unique role among nuclear receptors because
it forms heterodimers with other nuclear receptors (60,
287). Therefore, ligand activation has potentially pleiotropic effects on numerous biological pathways and has
been implicated not only in retinoid responses but also in
various metabolic pathways. RXR was originally identified as a novel retinoid-responsive transcription factor
(319). However, it turned out that RAR was more similar
to the TR than to RXR, suggesting that these two retinoid receptors are implicated in distinct pathways instead of representing a redundant retinoid signaling pathways. The lack of RXR␣ results in embryonic lethality in
homozygous embryos (249, 490). The abnormalities observed in RXR null mice were highly similar to the effects
of embryonic VAD (251).
One of the most enigmatic areas of the nuclear receptor
field is the existence of endogenous RXR activators and
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The nuclear receptor superfamily includes both steroid
and nonsteroid receptors (318). Most of these proteins
bind small lipophilic molecules, which either enter the
cells or are generated inside the cell (FIGURE 3). One-third
of the 48 human nuclear receptors form heterodimers
with RXR (78, 154). Among these RXR partners, there
are “classical” endocrine receptors, e.g., thyroid hormone receptor (TR), RAR, and VDR, which are activated
by high-affinity ligands, such as thyroid hormones, alltrans-retinoic acid, and 1␣,25-dihydroxyvitamin D3
[1,25(OH)2D3], respectively. Another group of RXR
partners consists of “adopted orphan” receptors, e.g.,
LXR, PPAR, and farnesoid X receptor (FXR). These receptors are activated mainly by metabolites, like oxysterols, fatty acids, and bile acids, which bind their receptors with low affinity (318, 473). Most RXR partners
require RXR as an obligatory dimerization partner for
DNA binding and transcriptional activity (FIGURE 3). As
a general principle, RXR heterodimers are believed to
reside in the nucleus bound to directly repeated response
elements with half site sequence AGGTCA or a variant of
it. RXR heterodimers are also believed to repress transcription in the absence of a ligand by recruiting a repressor complex. Upon ligand binding, transcriptional activation takes place as a result of a molecular switch replacing the corepressor complex with coactivator
complex(es) (368). In addition, ligand-bound receptors
can contribute to gene expression regulation without
binding DNA by a phenomenon termed transrepression.
In such cases, the receptor interferes with the activity of
other transcription factors by protein-protein interactions combined with posttranslational modifications.
Most prominently some of the anti-inflammatory activities of various RXR heterodimers are believed to use such
pathways (FIGURE 3).
discuss the interactions between the various pathways
and also how regulated ligand production contributes to
lipid signaling in these cell types.
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FIGURE 3. The principles of ligand generation and nuclear receptor action. A: biologically active ligands of
nuclear receptors can be derived from the surrounding environment, from the bloodstream, or can be
generated endogenously from their precursors. B: prototypic natural ligands of RXR and its partners are
shown. C: active ligand or its precursor enters the cell and gets into the nucleus where it binds the receptor.
Precursors go through enzymatic transformation(s). Liganded receptors can recruit coactivator and corepressor complexes to activate or repress transcription, respectively. For gene regulation, RXR heterodimers
bind specific DNA sequences, called hormone response elements. Alternatively, nuclear receptors might
interfere with the activity of other transcriptional factors, such as NF-␬B and AP-1.
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NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
Due to the fact that RXR works as a general dimerization
partner for many nuclear receptors (60, 261, 271, 287),
the other intriguing question concerning RXR is if there
is a heterodimer-independent RXR signaling. There are
in vitro data showing the presence of RXR homodimers
and tetramers, but under in vivo circumstances, no RXR
homodimer has been detected (84, 257, 542). This is
probably due to the strong binding capacity of RXR
monomer to its dimerization partners, and until such free
partner is present, no RXR-RXR interaction occurs. Our
recent gene expression profiling provided some clues
though regarding heterodimer-independent RXR signaling in DCs (508). Importantly, RXR seems to be an ancestral nuclear receptor from which many of the other
receptor families emerged. Ligand-binding domains of
the RXRs from different species show high degree of
similarity from jellyfish to human, and all are capable
of binding 9-cis RA (268). The more advanced arthropods including the insects have no RXR per se but express ultraspiracle (USP), a homolog of the RXR (195,
396). These suggest that RXR signaling appeared before
RAR, PPARs, and LXRs emerged, suggesting the persistence of autonomous RXR signaling. However, it is also
possible that evolution generated multiple partners for
the RXR, which can act only through its partners today.
B. LXRs Are Cholesterol Sensors
LXRs are involved in many cholesterol- and bile acid-related biological and pathological processes. LXR␣ and -␤
were cloned in 1994 based on sequence homology with
other nuclear receptors from a liver-derived cDNA library.
LXR␣ is highly expressed in the liver and at lower levels in
adipose tissue, intestine, lung, kidney, the adrenal glands,
and macrophages. LXR␤ is ubiquitously expressed (479,
750
565). Three LXR␣ isoforms have been reported so far, all
derived from the same gene via alternative splicing and
differential promoter usage (80).
As far as the regulation of the receptors are concerned, in
human but not in mouse cells LXR can induce its own
transcription (275, 295, 562). With the study of the promoter of LXR␣, CCAAT/enhancer-binding proteins (C/
EBPs) were reported to isotype and cell-type specifically
regulate LXR␣ expression (483). Remarkably, PPAR␥
can also induce the expression of LXR␣ (77). Interestingly, resveratrol, a naturally occurring polyphenol, was
also shown to regulate the expression of LXR␣ in human
macrophages, which could be a possible molecular explanation for some beneficial effects of polyphenols in cardiovascular diseases (468).
LXRs, similarly to PPARs, have large hydrophobic cavities that enable the binding of several different ligands
with lower affinity (58, 382, 530). A number of oxysterols have been identified as potential endogenous ligands for LXR. 24(S)-hydroxycholesterol, 25-hydroxycholesterol, 22(R)-hydroxycholesterol, and 24(S),25epoxycholesterol were shown to bind to and activate
LXRs at physiological concentrations (231, 284, 404).
Several other cholesterol metabolites have been reported
recently as potential LXR activators. For a detailed overview of LXR activator oxysterol metabolites, we refer to
a recent review (523). The search for endogenous LXR
activators placed oxysterol-producing enzymes in the focus of LXR research. One of the candidates, CYP27, is a
p450 enzyme that generates 27-hydroxycholesterol,
which can activate LXR (148, 230, 231, 498). CYP27 is
induced during macrophage development and is a direct
target for RAR, RXR, and PPAR␥ receptors (498).
Recently, Mitro et al. (339) assigned an unexpected role for
LXR, by showing that the receptor could function as a
potential glucose sensor and glucose could activate LXRdependent gene expression. However, others reported that
glucose is required for the transcription factor carbohydrate-responsive element-binding protein and that LXRs
are not necessary for the induction of glucose-regulated
genes in liver (120). Therefore, the contribution of glucose
to LXR activity requires further studies.
There are two widely used synthetic LXR agonists.
T0901317 is a nonsteroid LXR activator (435), which also
activates farnesoid X receptor (FXR) and pregnane X receptor (PXR) (214, 340). GW3965 is another potent nonsteroid LXR-selective activator (92).
These molecules usually do not discriminate between LXR␣
and LXR␤. However, LXR␤-selective agonists also exist.
N-acylthiadiazolines show increased selectivity for LXR␤
(345). Despite the selectivity and modest potency, the com-
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RXR-specific signaling. Several molecules have been
identified as potential endogenous ligands for RXR: 9-cis
RA (200), phytanic acid (290), and docosahexaenoic acid
(116), but none of these has been proven to be the bona
fide endogenous activator so far. Chambon and colleagues (66) excluded 9-cis RA as the RXR ligand during
keratinocyte differentiation by using a combination of
RAR and RXR conditional knockout mice. Perlmann
and colleagues (478) created a ligand detector mouse
line. They constructed transgenic lines using Gal-DNA
binding domain and RXR-ligand binding domain fusion
protein, a reporter gene, ␤-galactosidase containing Gal
binding sites in the promoter. X-gal staining of mouse
embryos revealed sites of ligand production. Staining of
specific regions in the spinal cord suggested the production of endogenous ligand. Luria et al. (310) used a similar system with green fluorescent protein as a reporter
(310). They also obtained reporter/RXR activity in spinal
cord and upon exogenous ligand treatment in the brain
and in the olfactory epithelium.
NAGY ET AL.
pound still induces cholesterol efflux from macrophages
with full efficacy.
The major function for LXR is the regulation of lipid metabolism at various levels. Activation of the receptor induces the expression of sterol regulatory element binding
protein 1c (SREBP-1c), a central regulator of fatty acid
synthesis (117, 434, 462, 579). In addition to SREBP-1c,
LXRs regulate several other enzymes involved in lipogenesis such as fatty acid synthase (239), acyl-CoA carboxylase
(512), and stearoyl-CoA desaturase 1 (551). When mice
were treated with LXR agonists, increased hepatic and
plasma triglycerides were observed, generating a serious
limitation on the therapeutic introduction of LXR agonists
(88, 174, 462).
Furthermore, LXR induced genes are involved in the uptake of
lipoprotein particles, like low-density lipoprotein receptor
(LDLR) (223) and scavenger receptor BI (SR-BI) (315, 582).
LXRs also control the expression of members of the ATPbinding cassette (ABC) superfamily of membrane transporters such as ABCG5 and ABCG8 (433, 536) in the
intestine or ABCA1 and ABCG1 in macrophages (99,
255, 435, 450, 464).
In vivo consequences of LXR activation have also been
studied. Administration of a synthetic LXR agonist
T0901317 induces expression of LXR target genes, like
ABC transporters and lipogenic genes, and results in increased triglyceride and phospholipid levels and in hepatic steatosis in mice (88, 174, 462). The same compound decreased atherosclerotic lesion development in
LDL receptor (LDLR) knockout mice (516). Another
LXR agonist, GW3965, induced expression of LXR target genes in the small intestine and also in macrophages
and increased reverse cholesterol transport by increasing
high-density lipoprotein cholesterol concentration (92).
Although LXR ligand treatment reduced atherosclerotic
lesion size in LDLR and apolipoprotein E (apoE) knockout animals (240), due to their effects on lipogenesis, the
potential benefit of LXR activators in the treatment of
atherosclerosis is limited (for details, see sect. VIIC).
C. PPARs Bind a Broad Range of Fatty Acids
and Diverse Synthetic Ligands
There are three members of the subfamily of PPAR.
PPAR␣ is expressed most prominently in the liver and
In this review we focus on one member of the family, PPAR␥,
because this has been shown most extensively to act as a modulator of macrophage and DC differentiation and function.
The first endogenous ligand for PPAR␥ was suggested to be
a prostanoid, 15-deoxy-⌬12,14-prostaglandin J2 (PGJ2)
(141, 260, 581). However, the amount of this compound
appeared to be too low or nondetectable in tissues for activating PPAR␥ (417). In macrophages it has been shown that
molecules from oxLDL can activate PPAR␥. These were
identified to be oxidized derivatives of fatty acids, like 9-hydroxyoctadecadienoic acid (HODE) and 13-HODE (325,
371, 461). Recent studies on PPAR␥ ligand binding revealed that it has a relatively large ligand-binding pocket
resulting in the possibility that two ligands can simultaneously occupy the pocket (225). Another unique feature of
PPAR␥ ligand binding is that oxo and/or nitrated fatty acids
can be coupled covalently to the receptor generating a more
potent activation than noncovalently bound ligands (225,
296, 544).
The essential role of PPAR␥ has been demonstrated in adipocyte differentiation (30, 57, 270, 445, 519), placental
development, and vascularization (30, 514, 515).
PPAR␥ deficiency results in embryonic lethality. A disturbance in terminal differentiation of trophoblasts and
placental vascularization leads to myocardial thinning
and death by E10.0 (30). Tetraploid-rescued mutant exhibited another lethal combination of pathologies, including lipodystrophy, fatty liver, and multiple hemorrhages (270, 445). Those PPAR␥ null mice that survived
to term were deficient for all forms of adipose tissue
providing evidence for the fundamental role of PPAR␥ in
adipogenesis (30). In macrophages PPAR ␥ regulates
many aspects of lipid/cholesterol metabolism and inflammation, which will be detailed below (77, 371, 437, 520).
By coordinating cholesterol uptake and efflux the recep-
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LXRs do not only regulate the synthesis of lipid molecules,
but their target genes are involved in the regulation of lipid
transport as well: lipoprotein lipase (LPL) (591), cholesteryl
ester transfer protein (309), phospholipid transfer protein
(PLTP) (67, 274, 313), apolipoprotein E (276), and the
apolipoprotein C-I/C-IV/C-II gene cluster (314).
regulates fatty acid oxidation (124). PPAR␥, which is
expressed in adipose tissue, macrophages, and DCs, regulates lipid uptake and storage (503, 521) and immune
responses. The ubiquitously expressed PPAR␤/␦ is implicated in fatty acid metabolism, mitochondrial respiration, thermogenesis, muscle lipid metabolism, and fibrotype switching (124). They all bind various nonesterified
fatty acids, polyunsaturated fatty acids, eicosanoids, or
prostanoids and regulate aspects of lipid metabolism in
which there is remarkably little overlap in spite of the fact
that they all bind to the same response element. A common feature of PPARs is that they are all targets of drug
discovery and have clear therapeutic utility. PPAR␣ and
PPAR␥ are the targets of lipid-lowering fibrates (256)
and thiazolidinediones (TZDs) used in insulin sensitization (521), respectively. Ligand for PPAR␤/␦ may be useful in muscle wasting syndromes (376).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
tor is a central player in foam cell formation, one of the
earliest steps during atherogenesis.
D. VDR Is a Classical Endocrine Receptor
According to the IUPAC-IUB, the term vitamin D should be
used as a general term to describe all steroids that exhibit
qualitatively the biological activity of cholecalciferol or vitamin D3 (1). In this way, vitamin D refers to many members of a group of secosteroids; these molecules have similar
structure to steroids, but one of the rings has been broken.
The two major physiologically relevant forms are vitamin
D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is the major naturally occurring form of the vitamin
in plants (204). Although vitamin D2 has been shown to
contribute significantly to the overall vitamin D status in
humans, and metabolized in a similar fashion as vitamin D3
(191, 209), for simplicity here we focus only on vitamin D3
metabolism. Humans get vitamin D3 from exposure to sunlight, from their diet, and from dietary supplements (204).
Vitamin D3 can be synthesized in the skin: 7-dehydrocholesterol is converted to pre-vitamin D3 when ultraviolet B
(UVB) penetrates the skin. Pre-vitamin D3 is then spontaneusly isomerized to vitamin D3. Vitamin D3 is not found in
plants and is present in low abundance in most animal
sources, except in fish species, fish liver oil, liver, and eggs
(119) which are rich in vitamin D3. Vitamin D3 is a prehormone, and it is activated by two hydroxylation steps (reviewed in Ref. 418). The first step occurs mainly in the liver
and converts vitamin D3 to 25-hydroxyvitamin D3
[25(OH)D3]. Circulating 25(OH)D3 is bound to vitamin D
binding protein. 25(OH)2D3 is the major circulating form
of vitamin D used by clinicians to determine the vitamin D
752
Mice deficient in VDR are viable, but display a phenotype
that resembles vitamin D-dependent rickets type II in
humans (135, 203, 297, 580). The phenotype includes
rickets and osteomalachia, elevated levels of and resistance to 1,25(OH)2D3, hypocalcemia, profound secondary hyperparathyroidism, total alopecia, and abnormal
skeletal muscle development. Remarkably, depending on
the ablated exons of VDR, there are differences in the
phenotype of different VDR⫺/⫺ mice (e.g., in fertility and
life span) (297, 580).
V. THE BIOLOGY OF RAR AND RXR IN
MACROPHAGES AND DENDRITIC
CELLS
A. Retinoids in Myeloid Development
RARs are expressed in nearly all hematopoietic lineages
(524) and play critical roles in hematopoiesis (248, 250). In
myeloid cells, RAR␣ is the dominant isoform; however,
RAR␤ and -␥ are also expressed at a lower level (114, 285).
RAR␤ can induce its own transcription (115); however, in
myeloid cells the silencing DNA methylation on the promoter of RAR␤ needs to be first erased for RAR␤ to be
expressed (125).
RAR contributes to myeloid differentiation through regulating expression of its target genes involved in the differentiation program. However, the contribution of RAR
to early myeloid development and to the granulocyte
lineage is more prominent than to the monocytic development (see below). RAR␣ induces C/EBP⑀ (87, 399,
575), CD18 (12, 63), CD38 (128), RTP801, a recently
discovered inhibitor of the mTOR pathway (155), interferon regulatory factor-1 (IRF1) (327), and leukocyte
alkaline phosphatase (158) and mediates cell cycle arrest,
a key phenomenon during differentiation (477, 545). MCSF, M-CSF receptor, G-CSF, GM-CSF, and GM-CSF
receptor were also reported to be induced by retinoic acid
in bone marrow stromal cells (111, 216, 373, 552).
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In contrast to RXR, LXR, and PPAR, the ligand of VDR
was discovered before the cloning of the receptor. The nutritional forms of vitamin D were identified, and their sturctures were determined during the 1920s and 1930s (reviewed in Ref. 119). 1,25(OH)2D3 (calcitriol), the active
form of vitamin D, was identified and synthesized in the
1970s (143, 205). The existence of the VDR was demonstrated in the 1970s by Brumbaugh et al. (55, 56), while
cloning of the cDNA encoding the human and rat VDR was
reported in the late 1980s (27, 61, 62). Vitamin D is essential for promoting calcium absorption in the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal mineralization of bone (119). It is
also required for bone growth and bone remodeling by
osteoblasts and osteoclasts. The classical manifestations of
vitamin D deficiency are rickets (in children), osteomalacia,
and osteoporosis (in adults) (204). However, a series of
experiments demonstrated that VDR is expressed in most
tissues in the human body, and vitamin D plays an important role in decreasing the risk of many chronic illnesses,
cancers, autoimmune diseases, infectious diseases, and cardiovascular disease (204).
status. The second step occurs primarily in the kidney and
forms the physiologically active 1,25(OH)2D3. Remarkably, many extrarenal tissues have the capacity to produce
the CYP27B1 enzyme responsible for the hydroxylation of
25(OH)D3. The inactivation of vitamin D metabolites is
also carried out by a hydroxylation step; CYP24A1 is the
key enzyme in 24-hydroxylation. Although nongenomic activity of 1,25(OH)2D3 is also documented, the majority of
its effect is thought to be carried out by VDR localized in the
nucleus. VDR is a high-affinity hormone receptor and a
nonpermissive partner of RXR. Ligand-bound VDR can
regulate gene expression via various molecular mechanisms, including direct activation where VDR-RXR most
effectively binds DR-3 (direct repeat with 3-bp spacer) response element (528).
NAGY ET AL.
Nonetheless, retinoids have a dual effect on developing
cells, either inducing maturation or cell death depending
on the cellular context and presence of other factors. In a
murine hematopoietic cell line, ATRA inhibited IL-6induced differentiation by downregulating IL-6 receptor
(395).
ATRA not only induces myeloid lineage but can also repress
erythroid differentiation by downregulating GATA1, a key
regulator of erythroid development (272).
When blood monocytes were cultured in the presence of
GM-CSF and ATRA, DC-like cells were generated in terms
of morphology, CD1a expression, adhesion, costimulatory
molecule expression, and T-cell activation (342).
As far as genetic evidence for the receptors involvement is
concerned. RAR␣ and -␥ knockout mice display a block
in granulocytic differentiation (236, 273). Dominant
negative RAR␣ blocks neutrophil development at the
promyelocyte stage (235, 525) and switches normal granulocyte/monocyte differentiation to basophil/mast cell
development (524). RAR was reported to act as a differentiation checkpoint switch at the promyelocytic stage of
granulopoiesis, resulting in granulocytic differentiation
(592). Following induction of myelomonocytic differentiation, induction of RAR␣ was observed (593). Retinoic
acid (RA) stimulates the maturation of myeloid precursors in cytokine-stimulated CD34⫹ cells (236). One of
the most studied examples of leukemia is acute promyelocytic leukemia (APL). In APL a t(15;17)(q22;q12)
chromosome translocation generates a PML-RAR␣ fusion protein that inhibits RAR, resulting in a block of
terminal differentiation of granulocytes (236, 241, 553).
Promyelocytic leukemia cell lines can be differentiated,
and APL patients can be successfully induced into remission with treatment of ATRA (93, 113, 131, 241, 470,
555). The translocation generates a PML-RAR␣ fusion
protein, which cannot release histone deacetylase
(HDAC) complex at physiological ATRA concentrations
leading to the maintenance of repressive chromatin
marks and corepressor binding (178, 193, 299). Dissoci-
However, the mechanism of PML-RAR␣-induced repression is more complicated. PML-RAR␣ was also shown to
interact with PU.1, a master regulator of hematopoiesis,
and the interaction results in the suppression of PU.1, which
leads to differentiation block (357). ATRA induces degradation of the PML-RAR␣ and restores PU.1 function. The
majority of PU.1 binding sites are in close proximity of
variably spaced RAR binding sites, which seemed to be
prerequisite for subsequent repression (546).
Besides the HDACs and PU.1, PML-RAR␣ mistargets
many chromatin modifiers resulting in the formation of
repressive marks, H3K27me3, H3K9me3, and DNA methylation (68, 125, 537). Despite these new findings, it is still
elusive what the crucial determinants for PML-RAR␣ binding to a specific region are. It could be the DNA sequence,
chromatin structure, interaction with other transcription
factors, or the combination of these.
In support of RXR’s involvement, expression of RXR␣ was
reported to correlate with the differentiation stage of myelomonocyte cells showing higher levels in more matured
cells (118). RXR-specific agonists were shown to overcome
the dominant negative effect of mutant RAR␣ and induce
myeloid differentiation (235). RXR agonists independently
from the RAR could lead to maturation of APL cells via a
crosstalk between RXR and protein kinase A (39). A combination of RAR and RXR activators could induce maturation of myeloid cell lines more efficiently than single agonists (470). However, others report that RAR and RXR
have distinct functions in myeloid differentiation by inducing either differentiation or apoptosis, respectively (40, 49,
333). Ligand activation of RARs in HL-60 cells resulted in
suppression of BCL-2 expression, whereas ligand activation
of both RARs and RXRs triggered the selective accumulation of tissue transglutaminase in the apoptotic HL-60 cells
(367, 369, 370). RXR␤ was also shown to perturb myeloid
differentiation when a dominant negative mutant was expressed in mice (493). Nevertheless, myeloid-specific deletion of RXR␣ had no major consequences on hematopoiesis
(439).
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There is evidence for crosstalk between nuclear receptor
pathways involving RAR. Probably through the induction
of C/EBPs RAR can induce PPAR␥ expression and potentiates the effects of PPAR␥ agonists on assisting macrophage
development (499). The PPAR␥ target gene CD36, a scavenger receptor on macrophages, is also regulated by RAR
(189). While ATRA is a more efficient inducer of granulocytic than monocytic development, vitamin D acts oppositely (32, 127, 266, 518). Vitamin D analogs are widely
used to induce monocytic differentiation. Interestingly, a
combination of retinoids and vitamin D may be more efficient, suggesting the possibility of a synergistic crosstalk
between the two pathways (45, 51, 54, 374).
ation of the corepressors NCoR or SMRT from PMLRAR occurs at high doses of ATRA, explaining the biological effect of pharmacological concentrations of RA
(178, 180, 193, 299). These results suggest that a failure
in HDAC release is the mechanism of APL. This was
further supported by the findings on PLZF-RAR fusion
protein, which is the result of a t(11:17) translocation
(335). Patients with this translocation are resistant to
ATRA treatment, since unlike PML-RAR, PLZF-RAR is
ATRA insensitive so HDAC and corepressors are not
released. Nevertheless, combination of ATRA and
HDAC inhibitors can induce relief of repression and admit differentiation. These findings established the role for
HDAC inhibitors in clinical therapy (85, 556).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
Therefore, probably due to the extensive combinatorial
possibilities of RAR regulation and the promiscuity of
RXR, the deconvolution of the exact role of RARs in myeloid cell differentiation is far from over.
B. Retinoids in Monocyte/Macrophage
Function
The mobility of monocytes/macrophages is affected by retinoids. 9-cis RA was shown to induce monocyte chemoattractant protein expression in human monocytic leukemia
cells (594). G-CSF and a novel RAR␣-specific agonist,
VTP195183, were shown to synergize and enhance the mobilization of hematopoietic progenitor cells from the bone
marrow (196). The effect of retinoids on cytokine production is also controversial in the literature.
There are pieces of evidence for both a pro- and anti-inflammatory role. The pieces of evidence for an anti-inflamatory
role are the following: ATRA was shown to inhibit TNF
and nitric oxide production in peritoneal macrophages
(334). In addition, ATRA enhanced the production of IL-10
while reduced the synthesis of IL-12 and TNF-␣ in LPSstimulated monocytes/macrophages (549). It was suggested
that ATRA repressed IL-12 expression via an interaction
between RXR and NF-␬B (366).
Another level of the anti-inflammatory effects of retinoids is
the attenuation of tissue damage at the site of inflammation.
ATRA could induce plasminogen activator inhibitor-2 production in blood mononuclear cells, which inhibited urokinase-induced extracellular proteolysis (346).
In DBA/1J mice with collagen-induced arthritis (CIA), retinoids improved the clinical course of the disease and reduced the production of inflammatory cytokines, immunoglobulin, and chemokines MCP-1, IL-6, IL-12, TNF, total
IgG, and IgG1 anti-collagen antibodies (384).
In a rat model of chronic allograft nephropathy, 13-cis RA
treatment decreased the number of infiltrating mononuclear
cells, their proliferative activity, and synthesis of MCP-1,
MIP-1␣, IP-10, RANTES, plasminogen activator inhibitor-1, transforming growth factor-␤1 (TGF-␤1), and collagens I and III (3).
754
There are also pieces of evidence to support a more proinflammatory and enhanced antimicrobial response. In a
randomized study on rats treated with RA, the severity of
tuberculosis infection was attenuated by increasing the
numbers of T cells, natural killer cells, and macrophages in
the lung and spleen, and the levels of IFN-␥, TNF, IL-1␤,
and iNOS were higher (573). RAR␥-deficient macrophages
exhibited impaired inflammatory cytokine production
upon TLR stimulation and defective immune response to
Listeria monocytogenes (132).
Clearly, a more systematic analysis of RARs contribution to
inflammatory paradigms needs to be carried out.
C. Retinoids in Macrophage Metabolism
The role of retinoids in macrophage metabolism is still
largely unexplored. A link between RAR, PPAR, and LXR
signaling is that CYP27, a mitochondrial P-450 enzyme
capable of generating 27-hydroxycholesterol, is under complex regulation by RAR, RXR, and PPAR␥ (498). The oxidized cholesterol derivative product of CYP27 could activate LXR to induce cholesterol efflux from foam cells,
thereby contributing to cholesterol removal from vessel
wall and reverse cholesterol transport (148, 231, 498).
Costet et al. (98) reported that the RAR␥:RXR heterodimer
induced the expression of ABCA1 in macrophages. In in
vivo studies, ATRA suppressed lesion development induced
by Chlamydia pneumoniae in hyperlipidemic C57BL/6J
mice while had no effect in uninfected animals (234). The
synthetic retinoid AM580 suppressed scavenger receptor
expression and macrophage foam cell formation in vitro
and prevented atherogenesis in apoE-deficient mice in vivo
(510). In carbohydrate metabolism, ATRA induces aldose1-epimerase (mutarotase), which catalyzes the interconversion of ␣ and ␤ hexoses, essential for normal carbohydrate
metabolism and the production of complex oligosaccharides. Through this pathway retinoids could affect energy
utilization and synthesis of cell-surface glycoproteins or glycolipids involved in cell motility, adhesion, and/or functional properties (398).
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The availability of natural and synthetic ligands for RAR
and RXR made it possible to generate a vast array of data
regarding monocyte/macrophage function. However, only
a fraction of these findings have been ascribed to receptor
activation using more extensive pharmacological and/or genetic approaches. Therefore, it is quite possible that some of
the effects are not receptor-dependent or do not require the
receptor’s genomic activity.
In a model of lupus nephritis in MRL/lpr mice, ATRA reduced lymphoadenopathy and splenomegaly and proteinuria. Although plasma IgG and anti-DNA antibody levels
and immunocomplex and complement deposition were not
affected, the numbers of infiltrating T cells and macrophages were decreased. Simultaneously, renal TGF-␤ level
was elevated (409). Similar results were obtained when rat
glomerulonephritis models were used (286, 457, 458). Both
liposomal and free ATRA could decrease the expression of
matrix metalloproteinase-9 (MMP-9) and induce its inhibitor, tissue inhibitor of matrix metalloproteinase 1 (TIMP1), in
bronchoalveolar lavage cells (142).
NAGY ET AL.
D. Effects of Retinoic Acid on DC Function
There is limited information about the expression of RARs
in DCs; however, a few studies indicated that at least some
of the isotypes of RAR and RXR proteins can be detected in
DCs.
Consistent with these results, Geissmann et al. (153) described that in the presence of pro-inflammatory stimuli
ATRA further enhanced the maturation of DCs; moreover,
it was suggested that the NF-␬B activation was responsible
for this effect. However, without inflammatory stimulation,
ATRA treatment itself elicited programmed cell death in
this DC model (153). Our data also indicated that synthetic
retinoid-treated DCs regulate a large number of genes and
pathways. For example, retinoid signaling coordinately regulated the CD1 gene family expression. Group 1 CD1 genes
(CD1a, CD1b, CD1c, and CD1e) were downregulated,
whilst group 2 CD1 (CD1d) was upregulated upon ATRA
treatment (504). Furthermore, our analysis revealed that
the enhanced expression of CD1d leads to an elevated natural killer T-cell activation capacity of these cells. We will
further discuss the CD1 gene family regulation on section
VIIF. Taken together, these observations suggested that activation of RAR positively modulates the immunogenicity
of DCs.
It is well known that retinoid signaling had an important
role for polarization of lymphocyte development (see sect.
XB); however, as we have described here, ATRA could also
instruct DCs, and this might also contribute for induction of
oral tolerance and regulation of the immune response.
However, other studies reported an opposite effect on RAR
activation. An early in vitro study revealed that even low
concentrations of ATRA exerted an inhibitory effect on
spleen-derived mouse DCs because these cells had an impaired T-cell stimulatory capacity (35). In line with this
finding, ATRA inhibited in vitro differentiation and maturation of DCs developed from human cord blood monocytes with impaired IL-12 and increased IL-10 production
(513). A recent report also indicated that ATRA-instructed
DCs had impaired IL-12 production; moreover, ATRA in
vivo might contribute to the IL-12 hypoproductive DC development (543). One study suggested that ex vivo ATRA
treatment also confers regulatory T cell inducing capacity of
We would like to note here that the role of LXR and PPAR␥
in macrophage lipid metabolism will be discussed in detail
in section VIIC.
VI. THE BIOLOGY OF LXR IN
MACROPHAGES AND DENDRITIC
CELLS
A. Contribution of LXRs to Macrophage
Biology
The role for LXR in macrophages appears to be focused to
three broad areas: complex regulation of basic lipid metabolism, modulation of immune responses, and the inhibition
of apoptotic pathways (FIGURE 4A).
LXR activity is modulated by the innate immune system,
and vice versa, LXR itself can modify cellular immune responses. A key observation showed that mice lacking LXR␣
were highly susceptible to Gram-positive intracellular
pathogen, Listeria monocytogenes infection (237). Bone
marrow transplantation experiments revealed that expression of LXRs in hematopoietic cells is required for this
effect. An important crosstalk between LXR and TLR signaling was uncovered in cultured macrophages as well as in
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In human monocyte-derived DCs, RAR␣ and RXR␣
showed the highest expression, and proteins of these receptors were also detected (504). Notably, mouse splenic DCs
expressed all RAR isoforms (320). These results suggest
that ATRA can exert a receptor-dependent effect on DCs.
Before the discovery of ATRA production by intestinal
DCs, the effects of retinoids on DC had already been investigated in detail. An early report indicated that in vivo administration of retinol-acetate or 13-cis RA increased the
number of DCs and macrophages in spleen; moreover, these
cells had an enhanced immunological function (252), suggesting that retinoid signaling had a positive effect on the
immunogenicity of DCs. A human study also indicated that
local treatment of ATRA on skin promotes the epidermal
DC (Langerhans cells) activation because these cells had an
enhanced HLA-DR, CD11c, and CD1c expression (338).
DCs (455). ATRA-treated swine monocyte-derived DCs
produce more TGF-␤ and IL-6; in addition, these authors
proposed that these cells could store and release ATRA, and
this retinoid signal also contributed for polarization of Tcell development (455). In mouse splenic DCs, zymosan
plus retinol treatment turned on endogenous ATRA production, and it was suggested that the endogenous ATRA
acted in an autocrine manner to suppress the production of
pro-inflammatory cytokines (IL-6, IL-12, and TNF-␣)
(320). Importantly, in this report, the authors started to
explore the potential mechanisms of this anti-inflammatory
effect. ATRA production stimulated the expression of
SOCS3, and the induction of this repressor protein contributed to the anti-inflammatory effects; moreover, ATRA signaling attenuated the activation of p38 MAP kinase (320) (FIGURE 5). It is still controversial how DC migration is regulated by retinoid signaling. One report suggested that
murine bone marrow-derived DCs have enhanced migratory capacity upon ATRA treatment in vivo via the enhanced production of MMP-12 (109). However, it was also
described that 9-cis RA or a synthetic retinoid negatively
regulated the migration capacity of DCs via the downregulation of CCR7 and CXCR4 chemokine receptors (539).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
aortic tissue in vivo by showing that microbial compounds
via TLR3 and TLR4 can inhibit LXR target gene expression
and cholesterol efflux in an IFN regulatory factor 3-dependent (IRF3) manner (72). LXR was also reported to exert
anti-inflammatory effects by inhibiting the expression of
several proinflammatory molecules such as iNOS, cyclooxygenase (COX)-2, IL-6, IL-1␤, MCP-1, MCP-3, and
MMP-9 in response to bacterial infection or LPS stimulation (71, 238). Therefore, LXR antagonizes inflammatory
gene expression downstream of TLR4 and also IL-1␤ and
TNF-␣-mediated signaling. On the more mechanistic front,
756
Glass and colleagues (157) demonstrated that a similar
mechanism of transrepression exists for LXR as reported
previously for PPAR␥ ligand binding results in SUMOylation of the receptor, which is recruited to the promoters of
inflammatory genes and inhibits LPS-induced corepressor
(NCoR) clearance. However, similar unresolved issues exist
in connection of this model as in the case of PPAR␥ (see
below). This would all point into the direction of LXR
being exclusively anti-inflammatory. However, an interesting observation was reported by Fontaine et al. while showing that short-term pretreatment by LXR agonists reduced
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FIGURE 4. The complex roles of nuclear receptors in macrophages. A: activation of LXR leads to cholesterol
efflux by increased removal and decreased uptake, inhibition of apoptosis, and attenuation of inflammatory
gene expression. B: PPAR␥ agonists increase cholesterol uptake via scavenger receptors, induce the LXR
pathway, and inhibit the inflammatory gene expression. C: two distinct activation mechanisms of macrophages.
Exposure to interferon (IFN)-␥ and tumor necrosis factor (TNF) leads to classical activation, whilst interleukin
(IL)-4 and/or IL-13 lead to alternative activation. STAT6 facilitates PPAR␥-regulated gene expression changes
in macrophages and DCs. D: activation of TLR1/2 heterodimer by Mycobacterium tuberculosis results in the
upregulation of VDR and CYP27B1 enzyme. The accumulating 1,25(OH)2D3 activates VDR leading to the
induction of cathelicidin and defensin beta 4 genes. The induction of defensin beta 4 requires convergence of
the VDR pathway and IL-1␤ signaling (not indicated). In human macrophages, vitamin D-mediated induction of
these antimicrobial peptides seems to be essential in combating Mycobacterium tuberculosis. 1,25(OH)2D3
regulates many other pathways in monocytes/macrophages. For simplicity, these are not indicated.
NAGY ET AL.
the inflammatory response induced by LPS; long-term pretreatment, however, resulting in an enhanced LPS response
(140) suggested that the crosstalk between LXR and TLR
signaling is more complex and likely to be context dependent. A difference exists in DCs as well regarding human vs.
mouse cells (see below).
Moreover, LXR␣ conferred the most protection and the
loss of this receptor correlated with macrophage apoptosis.
As a potential mechanism, Joseph et al. (237) identified
AIM (also known as SP␣, API6, and CD5L), a gene that
promotes macrophage survival, as a target of LXR␣ in
mouse macrophages. AIM also protects macrophages from
apoptosis when exposed to oxLDL, suggesting a role for
LXR as a macrophage survival factor during the development of atherosclerosis (237). Valledor et al. (531) reported
similar results by showing the upregulation of antiapoptotic
factors such as Bcl-XL and Birc1a and the inhibition of
proapoptotic elements such as caspases 1, 4/11, 7, 12, Fas
ligand, and DNase 1l3 by LXR (531).
B. LXR and DC Biology
Expression data suggested that LXR is also expressed in
DCs. Initially it has been established that LXR␣ is the dominant isoform in differentiating human DCs (156). Furthermore, it was also shown that LPS-induced maturation of
DCs is impaired together with some in vitro adhesion properties. This phenomenon was explained by the LXR-dependent regulation of actin-bundling protein fascin (156). Interestingly, recent studies also showed that endogenous
LXR ligands are produced by tumors. In turn, these compounds activate LXR and control the migratory capacity of
DCs to the tumor tissues in murine models. Downregulated
CCR7 expression was suggested as an explanation for this
effect. This finding suggests that LXR is being exploited by
tumors to support growth (538). However, there are striking differences between human and mouse DCs.
VII. THE BIOLOGY OF PPAR␥ IN
MACROPHAGES AND DENDRITIC
CELLS
A. PPAR␥ in Myeloid Development
PPAR␥ was shown to influence myeloid development (371,
499, 520). Activation of the receptor by natural or synthetic
agonists results in elevated expression of monocytic/macrophage markers such as CD14, CD36, CD11b, CD11c, and
CD18 on myeloid leukemia cells. PPAR␥ seems to regulate
later stages of the development favoring monocytic development; in addition, expression of the receptor correlates
with the developmental stage within the monocytic lineage
with highest level in the macrophages (499). Several groups
succeeded to differentiate macrophages from PPAR␥-deficient embryonic stem cells, indicating that PPAR␥ is dispensable for monocytic differentiation (76, 347). Its function is rather a modulator of the immune and metabolic
functions of the macrophages.
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Most recently, the Castrillo and Tontonoz laboratories
jointly demonstrated that LXR is involved in apoptotic cell
clearance (365). Macrophages play a role in the elimination
of apoptotic cells generated by the billions every day. The
uptake is a complex and not well understood process involving “find me” and “eat me” signals (424). Phagocytosis
of apoptotic cells by macrophages is significantly enhanced
upon LXR ligand addition and LXR-deficient macrophages
have a decreased capacity to take up apoptotic cells. Apparently, the lack of the apoptotic cell receptor Mer is responsible for some of these effects, which is identified as an LXR
target gene. In addition, LXR has been shown to directly
regulate RAR (425), and via this some additional factors
got implicated such as the retinoid-regulated enzyme, tissue
transglutaminase which has been linked to apoptotic cell
clearance (367, 509). Defective apoptotic cell uptake can
lead to chronic inflammatory conditions and autoimmune
diseases.
Our comprehensive analysis of LXR expression and activation provided further details on how activation of LXR
induces a differentiation program that effects the response
and phenotype of human DCs (522). This program includes
induction of costimulatory molecules, increases in proinflammatory cytokine production, and increases T-cell activation (FIGURE 5). Circulating blood CD1c⫹ DCs also responded to LXR ligand treatment, resulting in the increased
expression of LXR target genes. DCs similarly to other
professional APCs (antigen presenting cells) display a broad
array of TLRs to detect a wide array of pathogenic or damaged self structures. In principle, this results in activation of
NF-␬B signaling (226, 431). Importantly, other sensory
mechanisms are likely to participate in signal modulation.
While LPS interferes with LXR signaling in macrophages by
inhibiting the expression of its target genes (72, 238), it
appears that in DCs LPS increases the expression of target
genes. This suggests that LXR signaling is integrated in the
TLR signaling pathway by a context- and cell type-specific
manner. It is possible that DCs induce an increased LXR
response when exposed to specific TLR activators, provided
a ligand is available. This might be a hint about the existence of a potential mechanism for pathogene elimination
by an enhanced inflammatory response. The source and
origin of such ligand(s) are unknown yet. However, the fact
that the production of LXR activating lipids from tumors
could be detected (538) suggests that the inflammatory environment has a role in determining the receptor’s activity
also in vivo. If put together, the data obtained in macrophages and DCs strongly suggest the existence of an intriguing and so far largely unexplored crosstalk between TLR
and LXR signaling. This also means that LXR activation
may blunt or enhance host defense depending on the context. How cellular or immune context influences this crosstalk remains to be determined.
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B. Anti-inflammatory Role of PPAR␥ in
Monocyte/Macrophage
Although several potential mechanisms for the anti-inflammatory function have been assigned, the exact mechanism is
still elusive. The most accepted theory suggests that PPAR␥
agonists interfere with other transcription factors involved
in pro-inflammatory signal transduction pathways, such as
AP-1, STAT-1, NF-␬B, and NFAT. This mechanism requires a physical interaction between PPAR␥ and the other
transcription factor and subsequent inhibition, a process
called transrepression (402, 436). Transrepression is clearly
different from the canonical action of nuclear receptors,
when they bind to cognate DNA sequences and induce or
repress their target genes directly. The molecular mechanism of transrepression is poorly defined; however, it was
suggested that there is a ligand-dependent SUMOylation of
PPAR␥ that targets the receptor to corepressor complexes
on inflammatory genes’ promoters. This prevents the ubiquitination/proteasome-mediated degradation of repressor
We recently showed that PPAR␥ is dispensable for alternative macrophage activation per se and IL-4-induced gene
expression regulation; however, we found that IL-4 and its
effector transcription factor STAT6 is required for PPAR␥
activity in alternatively activated macrophages. We suggested an interesting mechanism for the crosstalk between
PPAR␥ and STAT6 by showing that STAT6 acts as a licensing factor for PPAR␥. STAT6 physically interacts with
PPAR␥ by binding the enhancers of PPAR target genes and
induces PPAR␥-mediated transcription (497).
FIGURE 5. Molecular events regulated by nuclear receptor ligands alter the antigen presenting function of dendritic cells. Events leading to
altered lymphocyte activation are depicted. Note that many genes regulated similarly in macrophages and DCs are not indicated. A: TLR2
signaling induces splenic DCs to express retinoic acid metabolizing enzymes and IL-10 and stimulate Tregs. All-trans-retinoic acid (ATRA) induces
suppressor of cytokine signaling-3 expression (SOCS3), which suppresses the activation of p38 and proinflammatory cytokines (for details see
text). B: the upregulation of Cd1d by RAR agonists leads to an enhanced iNKT cell expansion. PPAR␥ can turn ATRA by inducing the expression
of retinol and retinal metabolizing enzymes. Therefore, the effects of PPAR␥ and RAR agonists are similar in many aspects. The upregulation of
cathepsin D (CatD) lysosomal protease and CD1d leads to an altered lipid antigen presention and enhanced iNKT cell expansion. CD1d is
regulated by RAR, while CatD is regulated by both RAR and PPAR␥ in human monocyte-derived DCs. C: DCs reprogrammed with LXR agonist
have an increased response to TLR signaling and an augmented cytokine response resulting in proinflammatory T-cell responses. D: activation
of VDR leads to a tolerogenic DC phenotype, characterized by decreased expression of CD40, CD80, and CD86 costimulatory molecules, low
IL-12, and enhanced IL-10 and CCL22 secretion. The expression of antigen-presenting molecules is also lower, while the level of inhibitory
receptors, such as ILT3, is elevated.
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When PPAR␥ was identified in mouse thioglycolate-elicited
macrophages, its activators were shown to exert potent anti-inflammatory effects (437). Originally, they were shown
to inhibit macrophage responses to pro-inflammatory stimuli such as LPS or IFN-␥. Natural and synthetic PPAR␥
activators were shown to inhibit production of pro-inflammatory molecules, such as iNOS, MMP-9, and SR-A (437).
Similar effects were reported from human monocyte-derived macrophages (233), which led to the conclusion that
PPAR␥ agonists may act as potential anti-inflammatory
drugs. Over the last 10 years, PPAR␥ agonists have been
shown to exert anti-inflammatory effects at multiple levels.
For example, PPAR␥ agonists were shown to inhibit the
production of many proinflammatory cytokines like TNF,
IL-6, IL-1␤, IL-12, and gelatinase B (17, 89, 233, 293, 437,
438, 489, 561). Furthermore, PPAR␥ inhibits macrophage
migration and recruitment by repressing the transcription
of chemoattractant molecules such as MCP-1 and its receptor CCR2 (25, 31, 82, 188, 469). PPAR␥ agonists can also
induce the production of an anti-inflammatory cytokine,
IL-10 (258). Moreover, PPAR␥ suppresses TGF-␤ production indirectly by the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (280, 281).
complexes, which are required for gene expression (401).
This model, however, does not explain how ligand-bound
PPAR␥ can exert two opposite reactions simultaneously:
dissociation of the corepressor complex from the receptor
to induce target gene expression and recruitment of the
receptor to corepressor complexes associated with other
transcription factors to inhibit proinflammatory gene expression. Importantly, the negative regulatory role assigned
to PPAR␥ is not a direct transcriptional effect of the receptor but the consequence of the failed induction of inflammatory genes by other transcription factors activated upon
proinflammatory molecules, e.g., LPS (293, 402). Key in
vivo genetic evidence is still lacking to support this scenario.
Another possible mechanism is the sequestration of essential coactivators when their levels are limiting. Activation of
PPAR␥ upregulates PTEN, which inhibits phosphatidylinositol 3-kinase-mediated signaling cascades affecting cell migration, survival, and proliferation, providing a further possibility for suppression of inhibitory reaction (403). Another intriguing possibility to exert anti-inflammatory roles
comes from the link between PPAR␥ and the anti-inflammatory cytokine IL-4. Initially, Glass and colleagues (217)
showed that IL-4 induced PPAR␥ and an enzyme, 12/15lipoxygenese, capable of ligand production. However, the
amount of this compound (15d-PGJ2) appeared to be low in
tissues for activating PPAR␥ (417). Recently, Odegaard et
al. (387) reported that disruption of PPAR␥ in myeloid cells
resulted in impaired alternative macrophage activation and
claimed PPAR␥ to be requisite for the differentiation of
alternatively activated macrophages. This might not be generally applicable, because in another mouse strain, the receptor appeared to be dispensable (322).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
Remarkably, when the transcriptomes of macrophages
were analyzed with DNA microarrays, only a surprisingly
small number of regulated genes were found upon PPAR␥
activation (561). The question of macrophage PPAR␥ response has been addressed recently by us showing the requirement of IL-4 and STAT6 for the induction of PPAR␥
target genes (497).
PPAR␥ and/or its activators have been implicated in several
studies on inflammatory diseases. Several human diseases and
mouse models have been analyzed so far, and PPAR␥ agonists
were tested whether they inhibit disease progression. Here,
without going into the details, we refer to a previous review
where we summarized the effects of PPAR␥ activators in
airway and intestinal inflammation, autoimmune encephalomyelitis, myocarditis, arthritis, and dermatitis (500). For a
more detailed overview of PPAR␥ in airway inflammation, we
refer to earlier reviews by others (467, 481, 554).
Little evidence has been provided that these effects are really
PPAR␥-dependent and not nonspecific consequences of the
agonists. PPAR␥ knockout models have not been widely
involved in such studies, and the mechanisms of the antiinflammatory effects have also not been addressed in sufficient depth. However, there are a few reports on PPAR␥deficient animals. PPAR␥-deficient heterozygous mice displayed enhanced susceptibility to 2,4,6-trinitrobenzene
sulfonic acid (TNBS)-induced colitis (123).
5-Aminosalicylic acid (5-ASA), an anti-inflammatory drug
widely used in the treatment of inflammatory bowel disease,
had beneficial effects on colitis only in wild-type but not in
PPAR␥ heterozygous mice. It was shown that 5-ASA binds to
and activates PPAR␥ and exerts its anti-inflammatory effects
through the receptor (446). Targeted disruption of PPAR␥ in
760
macrophages (469) or colon epithelial cells (2) increased susceptibility of mice to dextran sodium sulfate-induced colitis.
C. Atherosclerosis: Role of LXR and PPAR␥
in Macrophage Metabolism
As detailed above, several lines of evidence support a central
role for macrophage-mediated inflammation in the pathogenesis of metabolic diseases. Macrophage infiltration and
the formation of foam cells is a prominent feature during
atherogenesis (FIGURE 6). Recently, both proinflammatory
classically activated and anti-inflammatory alternatively activated macrophages were shown to be present in fatty
streaks (52). PPAR␥ was shown to be expressed in lesion
macrophages (437, 520), and now a weak correlation was
found between the expression of PPAR␥ and alternative
macrophage markers (52). However, further studies are required to clarify the effect of inflammatory milieu on macrophages and PPAR␥ activity in the progression of the atherosclerotic plaque.
The function of PPAR␥ in foam cells has been characterized
in detail. PPAR␥ expression in macrophages could be further increased with oxLDL (371). PPAR␥ had a key role in
the regulation of oxLDL uptake into macrophages/foam
cells by inducing its direct target gene, the scavenger receptor CD36. Two components from the lipids in oxLDL,
9-HODE and 13-HODE, were identified as endogen activators and bona fide ligands of PPAR␥ (225, 371). These
results suggested the following model: macrophages internalize modified or oxLDL via scavenger receptors (e.g.,
CD36), which unlike LDL receptor are not downregulated
by high intracellular cholesterol levels. On the contrary,
oxLDL can further increase the expression of CD36 by
providing ligands for PPAR␥ and via this positive feedback
potentiates its own uptake. Oxidative modification of the
LDL particle endows it with the ability to bind scavenger
receptors and at the same time converts a component of the
particle, linoleic acid, into an effective activator of PPAR␥,
9- and 13-HODE.
OxLDL also induces SR-A expression via a PPAR␥-independent way. This regulatory circuit was termed gammacycle and suggested a novel mechanism how oxLDL contributed to foam cell formation and atherosclerosis.
These findings suggested the existence of a vicious cycle
(positive-feedback loop) leading to atherosclerosis and
assigned PPAR␥ a potential pro-atherogenic role. However, synthetic agonists of PPAR␥, the TZDs, are used in
treatment of type II diabetes. To dissect the in vivo contribution of PPAR␥ to the process of atherosclerosis,
Chawla et al. (77) generated mice lacking PPAR␥ in the
macrophages. Due to the fact that PPAR␥ total knockout
is embryonic lethal, chimeric mice were used for bone
marrow transplantation into irradiated animals. Transplantation of PPAR␥ null bone marrow into LDL recep-
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It is worth mentioning that PPAR␥ agonists can exert receptor-independent effects as shown when PPAR␥ knockout embryonic stem cells were differentiated to macrophages, which still elicited anti-inflammatory reactions in
response to PPAR␥ agonists (76, 347). Welch et al. (561)
also found that PPAR␥ macrophage-specific conditional
knockout mice still show anti-inflammatory effects upon
treatment with PPAR␥ activators. They suggested that
some of these effects could go through another nuclear receptor, PPAR␦, since at high concentrations PPAR␥ agonists can activate PPAR␦ as well (561). It was also reported
that 15d-PGJ2 can repress NF-␬B activity PPAR␥-independently via inhibiting I␬B kinase and/or by alkylating
p50 – 65 NF-␬B heterodimers (70, 489). Another PPAR␥independent mechanism involves the induction of suppressor of cytokine signaling (SOCS) 1 and 3, which results in
reduced phosphorylation of STAT1, STAT3, Janus kinase 1
(JAK1), and JAK2 in activated astrocytes and microglia
(232, 400).
NAGY ET AL.
proliferation
tor knockout animals resulted in significant increase of
the atherosclerotic lesion size. Additionally, Glass and
co-workers (293) reported that TZDs inhibited the development of atherosclerosis in LDL receptor-deficient
male mice. Similar results were shown by Z. Chen and
colleagues in apoE knockout mice, another murine atherosclerosis model (83). Targeted disruption of the
PPAR␥ gene from macrophages resulted in reduced total
plasma and HDL cholesterol levels, and cholesterol efflux was significantly decreased from macrophages elicited by thioglycolate in mutant mice (14). Based on these
observations, PPAR␥ can be considered an anti-atherogenic molecule (FIG. 6). Seeking the molecular mechanism
assigned a central role for PPAR␥ and LXR in regulating
cholesterol uptake and efflux during foam cell formation.
These generated a contradiction to the previous observations on PPAR␥-induced oxLDL uptake. This was resolved by showing that activation of PPAR␥ not only
results in cholesterol uptake, but it can also increase cho-
lesterol efflux from the macrophages. It was shown that
PPAR␥ could directly induce transcription of the oxysterol receptor LXR (77). PPAR␥ induces ABCA1,
ABCG1 expression, and cholesterol removal from macrophages through a transcriptional cascade via LXR␣.
The promoter of the ABCA1 gene was analyzed and
while LXR:RXR could activate it, PPAR␥:RXR heterodimer could not (77). They compared PPAR␥- and
LXR-induced cholesterol efflux and found that agonists
of both nuclear receptors induced cholesterol efflux, and
the combination of the ligands was additive. ABCA1 and
ABCG1 are members of the ATP-binding cassette family
of transporter proteins and are highly expressed in lipidloaded macrophages (536). Mutations in ABCA1 gene
result in Tangier disease, a disease characterized by
marked cholesterol accumulation in macrophages and
impaired cholesterol efflux from fibroblasts (48, 53,
449). Several studies reported that LXRs mediate cholesterol efflux by inducing cholesterol transporters ABCA1,
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FIGURE 6. Cellular events of early atherosclerotic lesions. A cross section of an atherosclerotic lesion is
depicted. Due to chemoattraction and activation signals, monocytes transmigrate from the lumen to the
subendothelial space and become macrophages. They acquire the capacity to take up modified lipoproteins
such as oxidized low-density lipoprotein (oxLDL) via scavenger receptors such as SR-A and CD36. Lipid uptake
leads to foam cell formation and eventually to the development of a fatty streak. Foam cells have the capacity
to eliminate cholesterol via ABC transporters (i.e., ABCA1) toward high-density lipoprotein (HDL) and also to
produce cytokines and contribute to further inflammatory reactions. Inset shows the cross section of an artery
with an atherosclerotic plaque. The effects of liver X receptor (LXR) and peroxisome proliferator-activated
receptor (PPAR) are indicated on the figure (for details, see text).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
762
this system results in cholesterol accumulation and contributes to atherosclerosis.
D. Role of Myeloid Cell PPAR␥ in Insulin
Resistance and Obesity
Recently, inflammation and inflammatory cells have been
described to be key regulators not only in atherosclerosis,
but also in obesity and insulin resistance (212). Due to the
fact that macrophages are located throughout the body including interfaces, they provide a potential role in the interplay between metabolic and inflammatory processes.
Chronic inflammation is now considered as a general phenomenon in obesity and diabetes mellitus. Infiltration of
adipose tissue with classically activated macrophages has
been recently described in obese conditions (243, 244, 472,
560, 571). However, the presence of alternatively activated
macrophages in adipose tissue and liver reduces tissue inflammation, increases oxidative metabolism, and improves
insulin resistance in obese mice (386).
It was suggested that overnutrition leads to the recruitment
of inflammatory macrophages to the adipose tissue, changing its original alternatively activated phenotype to classically activated one. This then further promotes obesity and
leads to insulin resistance. As reported by Odegaard et al.
(387), macrophage-specific PPAR␥ knockout mice were
predisposed to development of diet-induced obesity, insulin
resistance, and glucose intolerance. Furthermore, they reported the downregulation of genes in oxidative phosphorylation in both skeletal muscle and liver, which led to decreased insulin sensitivity in these tissues (387). Hevener et
al. (197) reported similar results: macrophage-specific
PPAR␥ knockout animals have glucose intolerance and insulin resistance in the skeletal muscle and liver accompanied
by increased expression of inflammatory mediators. Although these reports suggest important roles for macrophages in the development of insulin resistance and obesity,
they cannot be generally applicable, since Marathe et al.
(322) found PPAR␥, -␦, and LXRs dispensable for alternative activation and also their loss in macrophages did not
exert major effects on obesity or glucose tolerance. Similarly, rosiglitazone improved glucose tolerance in mice lacking macrophage PPAR␥, suggesting that other cell types
than macrophages are the primary mediators of the antidiabetic effects of PPAR␥ agonists (322).
E. PPAR␥ Expression in DCs
IL-4 is an important factor for the alternative activation of
macrophages; moreover, this cytokine positively regulates
PPAR␥ expression in macrophages (217). Interestingly,
IL-4 is a frequently used cytokine for the ex vivo generation
of human DCs from peripheral blood monocytes (452).
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ABCG1, and later ABCG5 and ABCG8 (99, 435, 535,
536). Cholesterol efflux from macrophages is likely to be
anti-atherogenic. By showing that LXR␣ is a direct target
gene of PPAR␥, activators of PPAR␥ were considered as
inducers of LXR-dependent cholesterol efflux. In this
modified gamma cycle, activation of PPAR␥ results in the
expression and activation of LXR, which in turn induces
ABC transporter expression and leads to cholesterol efflux from macrophages. However, the function of such
cycle depends on the presence of endogenous LXR activators. Since both PPAR␥ and LXR could be activated by
lipid components of oxLDL, it was hypothesized that
these nuclear receptors composed a transcriptional cascade that regulated macrophage response to oxLDL
(275). The fact that LXR is activated in macrophages
exposed to acetylated LDL (275), which is not supposed
to contain oxidized cholesterols, suggests the existence of
alternative ways to activate LXR. LXR:RXR heterodimers were originally identified as mediators of an
alternative retinoid signaling pathway (564, 565) showing that LXR:RXR heterodimer is highly permissive and
can be activated from either the RXR side by retinoids or
the LXR side by oxysterols (435). Due to the fact that
PPAR␥:RXR heterodimer is also permissive, one obvious
possibility for the dual activation of the two dimers
evokes from the RXR side. The other possible mechanism
is the generation of an LXR agonist. A number of oxysterols were identified as potential endogenous ligands for
LXR (230, 231, 284, 404). As Szanto et al. (498) showed,
both mechanisms are utilized in the macrophages. Retinoids via RAR and RXR and oxidized lipids via PPAR␥
can induce the transcription of a p450 enzyme, CYP27,
which generates 27-hydroxycholesterol, an endogenous
LXR activator (498) (see above). CYP27 is a mitochondrial enzyme involved in the alternative bile acid synthesis pathway (19, 65, 414, 447, 448) and is expressed in
addition to the liver in the lung and also in macrophages
(26, 46). It has been also associated with atherosclerotic
lesions (102, 219). A mutation in the enzyme results in a
rare sterol storage disease, cerebrotendinous xanthomatosis, characterized by xanthomas in tendons and also in
the CNS leading to ataxia, spinal cord paresis, neurological dysfunctions, normolipidemic xanthomatosis, and
accelerated atherosclerosis (47, 64, 341). Taken together, oxLDL not only provides ligand for PPAR␥ activation, but PPAR␥ also induces LXR function via two
mechanisms: 1) it induces the receptor and 2) it induces
an enzyme that generates ligand for it. A recent discovery
of LXR regulation of Inducible Degrader of LDL receptor (Idol) further reinforces the notion that activation of
LXR leads to increased efflux by also inhibiting further
uptake (587). The consequence of the uncovered network
is increased cholesterol turnover in the macrophages with
induction of reverse cholesterol transport. Any disturbance in the activity of the participants or overload of
NAGY ET AL.
RXR␣, the dimerization partner for PPARs, was detected in
monocyte-derived DCs (504), and it was reported that RXR
agonist 9-cis RA has a similar phenotype as PPAR␥-specific
ligands (585), suggesting the PPAR␥:RXR heterodimer can
be activated from both sides of the heterodimer. Taken
together, these observations revealed that various subsets of
DCs expressed PPAR␥, suggesting a role in modulation of
differentiation and/or activation of DCs.
F. Modulation of the Immunogenicity and
Lipid Metabolism of DCs by Activation of
PPAR␥
PPAR␥ can be activated with synthetic PPAR␥ agonists in
DCs (for example, with rosiglitazone or troglitazone) as
shown by the induction of several generic PPAR␥ target
genes (CD36, FABP4/aP2) after ligand administration (502,
503). Much effort has been applied over the past few years
to characterize the effects of the activation of PPAR␥ in
DCs. Most of these studies investigated the immune function of DCs by assessing their cell surface phenotype, cytokine production, and T-cell activation capacity. First, it was
suggested that PPAR␥ activation did not change the immunogenicity (T-cell activation capacity) of murine splenic
DCs, although these cells had impaired IL-12 production
(137). A similar finding was obtained when the same investigators studied the effects of PPAR␥ ligand on human
monocyte-derived DCs. PPAR␥ agonist-treated DCs had
impaired IL-12 production; moreover, expression of IP-10
and RANTES chemokines were also downregulated, while
several cytokines were unaffected (IL-6, IL-10, IL-1␤, and
TNF-␣) (170). In addition, PPAR␥ agonists positively regulated CD86 expression whilst CD80 expression was
downmodulated. These findings suggested that PPAR␥ activation modulated the polarization of DC-dependent immune response. The authors suggested that activation of
PPAR␥ pathway in DCs favors the differentiation of naive T
cells into type 2 cytokine-producing T lymphocytes (Th2
cells), since Th1 polarizing factor IL-12 profoundly decreased; in addition, the diminished production of IP-10
and RANTES may participate in the preferential recruitment of Th2 rather than Th1 lymphocytes. Notably, in
these studies, cells were challenged with PPAR␥ activators
during the maturation of DCs; however, some other reports
investigated the ex vivo effect of PPAR␥ ligand during the
course of DC development from monocytes. In these cases,
ligand treatment had a profound inhibitory effect on the
immunophenotype of DCs. Nencioni et al. (378) described
that activation of PPAR␥ affected DC immunogenicity and
reverted them to a less stimulatory mode. They confirmed
the impaired IL-12 production, diminished CD80, and enhanced CD86 expression; however, several other cytokines
(IL-6, IL-15, TNF) were also downregulated in the presence
of PPAR␥ ligand (378). In addition, these cells expressed
less CD40 and CD83, suggesting that PPAR␥-activated
DCs conferred an impaired immunogenicity. Consistent
with these findings, PPAR␥ ligand treatment severely
blunted the T-cell activation capacity of these cells (378).
This report also described that PPAR␥-instructed DCs expressed less CCR7, an important chemokine for DC migration. In line with this finding, murine Langerhans cells had
an impaired migration capacity upon in vivo administration
of PPAR␥ agonist (22). Interestingly, a reduced expression
of CCR7 was also detected in bone marrow-derived,
ovalbumin-pulsed DCs, and PPAR␥ activation also decreased the migratory capacity of these cells (186). In addition, in vivo administration of the PPAR␥ agonist pioglitazone reduced the tipDC (TNF/iNOS producing inflammatory DC) accumulation in lung upon H5N1 influenza A
virus infection (16). It is possible that a PPAR␥-dependent
impaired migration is responsible for the reduced recruitment of this DC subtype to the airway. The diminished DC
immunity was also described in ex vivo murine DC models.
Bone marrow-derived, PPAR␥ ligand-treated DCs also had
an impaired T-cell activation capacity (262). Importantly,
the negative effects of PPAR␥ ligand on DC priming were
not observed in PPAR␥ knockout DCs, suggesting that
these repressive effects were receptor dependent (262).
In the macrophage section, we have already discussed in
detail the potential mechanisms of the anti-inflammatory
effects of PPAR␥ activators. It was suggested that PPAR␥
interfered with the NF-␬B pathway, which is important for
the activation/maturation of DCs (397). Indeed, PPAR␥
agonist-treated, monocyte-derived DCs had diminished nuclear localization of c-Rel, a component of NF-␬B (23, 378).
In addition, it seems that the MAP kinase pathway was also
affected: PPAR␥-instructed DCs showed impaired phosphorylation of ERK kinase, and diminished phosphorylation of P38 was detected upon TLR4-dependent maturation
(23). NF-␬B binding and impaired MAP kinase signaling
pathway was also described in murine bone marrow-derived DCs, suggesting that it is a general repressive mechanism in DCs (262). Interestingly, activation of PPAR␥ leads
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Remarkably, a global gene expression profile analysis revealed that PPAR␥ was one of the highly upregulated transcription factors during IL-4/GM-CSF-driven monocytederived DC differentiation (279). The elevated expression
of PPAR␥ was confirmed with more detailed transcript and
protein analyses. Gosset et al. (170) described that PPAR␥
RNA and protein are highly upregulated upon human
monocyte-derived DC differentiation, and later, others also
observed robust induction of PPAR␥ upon DC development from monocytes (378, 502). In addition, our immunohistochemical analysis revealed that in human lymphoid
tissue (tonsil) some of the S100 positive cells were also
PPAR␥ positive, suggesting that in vivo, at least a subset of
DCs also express PPAR␥ (502). PPAR␥ expression in DCs is
not human specific, since CD11c splenic DCs also express
this receptor (137) and PPAR␥ protein was also detected in
murine bone marrow-derived DCs (186).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
to the upregulation of the coinhibitory molecule B7H1, and
this inhibitory signal contributed for impaired activation of
CD8⫹ T cells (263), suggesting that this mechanism is also
part of the anti-inflammatory effects of PPAR␥. In summary, several lines of evidence suggested that activation of
PPAR␥ has an adverse effect on DC immunity, maturation,
and migration.
The physiological role of this scavenger receptor on DCs is
still controversial. It was suggested that CD36 had an important role for apoptotic cell uptake and cross presentation of antigens to cytotoxic T cells in human DCs (15).
However, the CD36-deficient animal model revealed that
CD36 is not essential for cross presentation of cellular antigens in vivo (59, 463). The other well-established PPAR␥
target is aP2 (alternative name FABP4). This adipose-specific fatty acid binding protein is a very abundant protein in
fat cells (192). Remarkably, in monocyte-derived DCs, this
transcript showed the highest upregulation upon PPAR␥
ligand treatment (502); in addition, the protein level was
also strongly induced in PPAR␥-activated DCs (505). The
potential role of this lipid binding protein in DCs is poorly
characterized; however, bone marrow-derived DCs obtained from FABP4/aP2-deficient animals had impaired cytokine production (IL-12, TNF) and diminished T-cell activation capacity, suggesting that at least a low level of this
protein positively regulated DC immunogenicity (443). Interestingly, one member of the ABC transporter family was
directly regulated by PPAR␥ in monocyte-derived DCs. Our
data revealed that PPAR␥ induced the expression of
ABCG2 in differentiated human DCs; moreover, we identified a specific enhancer region containing three PPAR response elements in the upstream region of the ABCG2 gene
(506) The ABCG2 protein is highly expressed in the plasma
membrane of several drug-resistant cell lines, where it has
been shown to extrude anti-tumor drugs (454); consistent
with these findings, our results indicated that PPAR␥-instructed DCs had an enhanced xenobiotic extrusion capacity (526).
Interestingly, besides the upregulation of individual
genes, our global gene expression profile analyses revealed that a gene cluster and a few signaling pathways
were also modulated in PPAR␥-instructed DCs. We
764
Our global gene expression analysis also indicated that
PPAR␥ activation might modulate the lipid metabolism
of DCs. A time course experiment of PPAR␥ ligand treatment revealed that genes involved in lipid metabolism
comprised the primary class of transcripts changed in
early stages of DC differentiation, while genes linked to
immune responses were altered at later phases of DC
development. These results suggested that PPAR␥ primarily modulated the lipid metabolism/transport in DCs
and immune response-related genes are indirectly regulated (505). It is still unexplored how the two pathways
are connected in DCs, but in macrophages it was suggested that lipid metabolism and immunity are interconnected (533).
In summary, activation of the PPAR␥ pathway in DCs
has detrimental effects; it is important to emphasize that
most of these effects are receptor dependent, since these
could be reverted by a PPAR␥ antagonist (GW9662) (21,
502). More importantly, conditional knockout data also
revealed the receptor dependency (262). In addition, we
found that several genes showed impaired induction/repression
in PPAR␥-activated DCs obtained from patients harboring
mutated PPAR␥ receptors (11, 505). In the future it would
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However, in addition to these negative effects on DC development, we and others identified several pathways and target genes, which were positively regulated by PPAR␥ agonists. PPAR␥-activated monocyte-derived DCs had an enhanced FITC-dextran uptake capacity (23, 502). PPAR␥
ligand treatment resulted in increased mannose receptor
expression in mouse DCs, which consequently led to enhanced mannose receptor-mediated endocytosis of soluble
ovalbumin antigen (263). CD36 was one of the first identified PPAR targets in DCs (170, 378), and this receptor is
implicated in antigen uptake.
found that the lipid antigen presentation capacity of DC
appears to be impacted by PPAR␥ activation via the coordinate regulation of CD1 proteins. CD1 proteins are
MHC class I-like molecules that present lipid antigens to
T cells; thus CD1s play an important role in acquired
immunity. These proteins are divided into two groups:
group 1 comprises CD1a, CD1b, CD1c, and CD1e and
presents antigens derived from pathogenic microbes;
group 2 contains only CD1d that is considered to present
self-glycolipids, and this protein is necessary for generation and expansion of iNKT (invariant natural killer T)
cells (36, 254). We detected a reduced expression of
CD1a, -b, -c, and -e and an enhanced expression of CD1d
in human PPAR␥ activated monocyte-derived DCs (502).
The functional consequence of the elevated expression of
CD1d was the selective expansion of iNKT cells (502).
Recently, further mechanistic insights have been gained
into this process by demonstrating that a lysosomal aspartyl protease, cathepsin D, is also regulated by PPAR␥
and also by RAR, and it contributes to the lipid antigen
presentation process by cleaving ProSaposin and thereby
facilitating lipid antigen processing (375) (FIGURE 5). We
also found a connection between PPAR␥ and RAR pathways on CD1d regulation: PPAR␥-activated DCs had an
enhanced ATRA production capacity, and some of the
PPAR␥-dependent gene induction (CD1d and TGM2)
was turned out to be indirectly regulated via the activation of RAR␣ nuclear receptor (506). We will discuss the
potential connection between PPAR␥ and retinoid pathways in DCs in section XA.
NAGY ET AL.
be important to characterize the effects of PPAR␥ activators
on DC development and function in vivo.
G. Natural/Endogenous Ligands for
Modulation of the PPAR␥ Pathway in DCs
oxLDL contains several lipid species, which were described
as PPAR␥ ligands (110, 371). DCs might also be engaged
with oxLDL, and several reports documented the effects of
oxLDL on DC development. We found that oxLDL indeed
induced the expression of PPAR␥ targets (FABP4/aP2,
CD1d); however, this effect was much less profound as a
synthetic PPAR␥ activator (502). Some of the regulated
genes were also induced by retinoids; thus it is possible that
upregulation of CD1d was mediated by the retinoid content
of the oxLDL (504). On the other hand, oxLDL promoted
the maturation of DCs (101), and probably this is a PPAR␥independent signaling pathway since the pro-inflammatory
lysophosphatidylcholine (LPC) could mediate this effect
through the activation of a G protein-coupled receptor
(100). Taken together, these results demonstrate that complex lipids like oxLDL have detrimental effects on DC activation and probably multiple pathways are involved.
There are several other lipid compounds that were considered as PPAR␥ agonists in DCs. For instance, pollen grains
contain pollen-associated lipid mediators; among these, E1
VIII. THE BIOLOGY OF VDR IN
MACROPHAGES AND DENDRITIC
CELLS
A. Vitamin D and the Immune System: An
Overview
The immunomodulatory role of vitamin D first was demonstrated on T cells and B cells (289, 350, 440). The
expression of VDR was documented in many human and
murine immune cells, most importantly in macrophages,
monocytes, DCs, T cells, B cells, and iNKT cells. Natural
and synthetic VDR agonists can modulate a broad range
of immune responses in these cells, and immunosuppressive effects of 1,25(OH)2D3 and its analogs also have
been documented in in vivo animal models of immunemediated diseases such as autoimmune diabetes, experimental autoimmune encephalomyelitis, and allograft rejection.
The regulatory role of 1,25(OH)2D3 on T cells and B cells is
complex. 1,25(OH)2D3 inhibits T-cell proliferation and
downmodulates the expression of IL-2, IFN-␥, and CD8⫹
T-cell mediated cytotoxicity, while IL-4 production is enhanced (44, 182, 288, 289, 332, 350, 428, 440, 441, 532).
1,25(OH)2D3 blocks the induction of Th1 cell and Th17
responses, while promoting Th2 cell and Treg responses
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In the previous section we have demonstrated that activation of PPAR␥ exerted detrimental effects on differentiation
and immunogenicity of DCs. Most of these studies used
high-affinity, synthetic PPAR␥ activators; however, it is unclear whether the natural/endogenous PPAR␥ ligands can
regulate these pathways in DCs or not. It is generally accepted that high concentration of polyunsaturated fatty acids, oxidized fatty acids, oxidized phospholipids, and several prostanoids can serve as natural ligands for PPAR␥.
Interestingly, some of these lipid mediators also regulate the
immune response; more importantly, migratory DCs might
be exposed or even produce these lipid mediators. The first
lipid mediator was prostaglandin D2 (PGD2) as potential
activator of PPAR␥ in DCs. Angeli et al. (20) described that
PGD2 inhibited the migration of Langerhans cells. Synthetic
PPAR␥ agonists had similar inhibitory effects (21), suggesting that it might be a receptor-dependent effect. PGD2 binds
to cell surface receptors, and it is unlikely to be a PPAR␥specific ligand. However, 15-dexoxy PGJ2 (15d-PGJ2), the
dehydration end product of PGD2, is a high-affinity ligand
of PPAR␥ receptor (141, 260). Interestingly, administration
of 15d-PGJ2 had similar effects as troglitazone or rosiglitazone (well-established PPAR␥ activators) on DC differentiation and activation (378). However, it is worth mentioning
that this lipid compound had some PPAR␥-independent
effects (489); moreover, the physiological role of this molecule is still debated due to its low concentration in vivo
(417).
phytoprostane (PPE1) was suggested to be an activator of
PPAR␥ (160). It is worth mentioning that this compound
had a PPAR␥-dependent and -independent effect on DCs
(160). Polyunsaturated fatty acids are natural ligands of
PPAR␥. Consistent with this notion, doxosahexaenoic acid,
a polyunsaturated fatty acid, had a similar effect as synthetic PPAR␥ activators on DCs (586). The authors assumed that these effects were mediated by activation of
PPAR␥. However, this compound also binds RXR, suggesting that it can activate both partners of the PPAR:RXR
heterodimer (586). Interestingly, our data indicated that the
serum itself could modulate the activation stage of PPAR␥
in developing DCs. When monocyte-derived DCs were differentiated in human serum instead of fetal bovine serum,
an elevated expression of several PPAR␥ targets (FABP4/
aP2, ABCG2) was detected, and this could be reverted with
PPAR␥ antagonist, suggesting this to be a receptor-mediated process (502, 506). A more systematic gene expression
profile analysis revealed that in human serum-cultivated
DCs, a similar set of transcripts was upregulated as in synthetic PPAR␥ ligand-treated cells, indicating that a high
affinity or high concentration of ligand might be present in
or generated from human serum (505). The nature of such
putative ligand is poorly defined; however, one study suggested that human serum-derived cardiolipin and lysophosphatidic acid might be responsible for the enhanced activation of PPAR␥ (291).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
(350). In addition to its inhibitory effects on T cells,
1,25(OH)2D3 decreases B-cell proliferation plasma cell differentiation and IgG secretion (81, 289, 350) acting directly
on B cells, or via antigen presenting cells and/or T cell help
(81, 350, 360, 471, 534). A recent study documented that
VDR expression is required for the normal development
and function of iNKT cells (583).
In immune cells, 1,25(OH)2D3 regulates the gene expression by various molecular mechanisms. CYP24A1,
CAMP, PPAR␦, and ALOX5 are upregulated directly by
VDR:RXR (79, 130, 167, 480). Some immune functionrelated genes, e.g., IER3 and RelB, are downregulated
directly via negative response element (126, 221). Ligand-bound VDR can also act by antagonizing the “inflammatory” transcription factors like NFATp/AP-1 and
NF-␬B, which results in decreased expression of IL-2 and
IL-12, respectively (106, 511). 1,25(OH)2D3 can also
regulate gene expression by indirect mechanisms, by alteration of the level of enzymes, transcription factors,
and coregulators (532).
B. Effect of 1,25(OH)2D3 on Monocytes/
Macrophages
The immunosuppressive effects of vitamin D on monocytes and macrophages are intensively investigated and
well documented. 1,25(OH)2D3 inhibits the expression
of all three subtypes of MHC class II antigens (HLA-DR,
-DP, and -DQ) (572). VDR agonists exert strong immunosuppressive effects on IFN-␥-stimulated (but not on
LPS-acivated) murine macrophages (194). Moreover,
1,25(OH)2D3 treatment leads to the inhibition of the
listericidal activity, the inhibition of phagocyte oxidasemediated oxidative burst, and the suppression of IFN-␥induced genes, including CCL5, CXCL10, CXCL9,
Fcgr1, Fcgr3, and TLR2 (194).
However, many studies described the effects of 1,25(OH)2D3
distinct from its immunosuppressive capacity. Most importantly, 1,25(OH)2D3 or its analogs can initiate the differentiation of myeloid progenitors into macrophages (90, 266,
391). 1,25(OH)2D3 can also enhance the phagocytosis by
monocytes (572). Administration of 1,25(OH)2D3 to mitogen-stimulated mononuclear cells caused an increase in
prostaglandin E production (267). When added to peripheral blood monocytes, 1,25(OH)2D3 augmented IL-1 pro-
766
Remarkably, 1,25(OH)2D3-treated macrophages exhibit
enhanced antimicrobial activity (103, 304, 444), because
1,25(OH)2D3 regulates genes encoding antimicrobial proteins, such as the cathelicid and defensin B. The antibacterial effects of macrophages will be discussed in details in
section VIIIF.
C. Effect of 1,25(OH)2D3 on DCs
A number of studies provided evidence that 1,25(OH)2D3
inhibits differentiation, maturation, and immunostimulatory capacity of human and mouse DCs (10, 43, 150, 176,
177, 405, 412). The effect of 1,25(OH)2D3 on inhibiting
the maturation of DCs was dependent on VDR (176). Molecular characteristics of 1,25(OH)2D3-treated DCs include
low surface expression of MHC-II and costimulatory molecules (CD40, CD80, CD86); upregulation of inhibitory
molecules (ILT3) decreased production of IL-12 and enhanced secretion of CCL22 and IL-10 (43, 150, 176, 177,
405– 408, 412). The inhibition of immunogenic pathways
and the induction of “tolerogenic” molecules all together
lead to a tolerogenic DC phenotype (352, 407). The tolerogenic properties of DCs induced by 1,25(OH)2D3 treatment
are usually associated with the induction of Treg cells
(FIGURE 5). However, tolerogenic pathways initiated by
DCs can be also manifested in effector T-cell death and
T-cell anergy. According to our study, 1,25(OH)2D3 can
regulate transcription of several immune function-related
genes, including genes the altered expression of which
contributes to tolerogenic DC phenotype, independently
of the differentiation process (507). The capacity of
1,25(OH)2D3-treated DCs to induce CD4⫹ CD25⫹ regulatory T cells that, besides its direct effects on T cells, can limit
ongoing inflammatory responses make this ligand or its
analogs (alone or in combination with other anti-inflammatory compounds) potential therapeutic targets (see below).
D. Endogenous Production of 1,25(OH)2D3
in Macrophages and DCs
1,25(OH)2D3 is ⬃1,000 times less abundant in human
serum than its precursor, 25(OH)D3 (206 –208). This
concentration is insufficient to turn on 1,25(OH)2D3induced transcriptional changes in monocyte-derived
DCs (507) and most likely in macrophages. Remarkably,
a number of studies documented that both macrophages
and DCs could produce 1,25(OH)2D3 from its precursors, suggesting that 1,25(OH)2D3 could act by an autocrine or paracrine fashion in these cells (8, 147, 171,
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The in vitro effects of 1,25(OH)2D3 and its analogs on
antigen presenting cells were documented by a number of
studies on different macrophage and DC types. These studies demonstrated that cell subtypes could exhibit significant
differences (e.g., conventional DCs vs. plasmacytoid DCs).
It should be also noted that 1,25(OH)2D3 can play a different role in humans (daytime creatures that can synthesize
vitamin D3 in the skin) and mice (nocturnal animals).
duction (44). In addition, 1,25(OH)2D3 alters oxidative
metabolism of monocyte/macrophage as demonstrated by
human blood monocytes, which developed enhanced competence of secretion of H2O2 in the presence of 1,25
(OH)2D3 (91).
NAGY ET AL.
E. The Potential Role of Endogenously
Produced 1,25(OH)2D3 in Triggering
Negative-Feedback Mechanisms
The fact that 1,25(OH)2D3 has immunosuppressive capacity suggests a potential negative-feedback mechanism
in antigen-presenting cells (133, 182, 194, 198). According to this scenario, besides initiation of immunogenic
responses, inflammatory stimuli can also induce the generation of a negative signal, 1,25(OH)2D3, that limits the
extent of the immune responses and helps to avoid overstimulation (4, 95, 133, 194). As we could see in section
VIII, B and C, endogenously produced 1,25(OH)2D3 can
inhibit inflammatory pathways by various mechanisms.
A recent study suggested another potential mechanism,
demonstrating that 1,25(OH)2D3 can induce hyporesponsiveness to pathogens by downregulating the expression of TLR2 and TLR4 on monocytes (4, 451). The
hypothesis of such a negative-feedback loop is supported
by studies on VDR knockout animals. For example, VDR
knockout mice are more resistant to intracellular protozoan Leishmania major infection than their wild-type
littermates (133). Moreover, VDR knockout mice have
larger subcutaneous lymph nodes than their wild-type
littermates and contain increased number of mature DCs
(176), most likely due to the lack of negative feedback of
DC maturation.
F. Antimicrobial Role of 1,25(OH)2D3 in
Macrophage
Detection of pathogens and initiation of immune responses are dominantly triggered by TLRs and other pattern recognition receptors (13, 226, 331, 415, 576).
TLR2 activation by bacterial lipoproteins leads to killing
of intracellular Mycobacterium tuberculosis in both
mouse and human macrophages, albeit via distinct mechanisms (304, 517). In mouse macrophages, activation of
TLR2/1 triggers the production of iNOS and consequently the release of nitric oxide (517). In human macrophages, the mechanism is nitric oxide-independent.
The activation of TLR2/1 induces the expression of both
VDR and CYP27B1, leading to an increased expression
of VDR target genes, including antimicrobial peptides,
cathlicidin, and defensin B2/4 (5) (167, 304, 548) (FIGURE 4). These peptides efficiently kill intracellular Mycobacterium tubercolosis. [TLR2/1-mediated expression of
defb4 requires convergence of the IL-1␤ and VDR pathways (303).] Cathelicidin is not only necessary but also
seems to be sufficient for vitamin D-mediated human
antimicrobial activity (305). However, it is possible that
this antimicrobial peptide is not the only mediator of antimicrobial activity (304). The identified 1,25(OH)2D3dependent antimicrobial mechanism could explain a series of previous observations (302, 304, 305). First, both
heliotherapy (sun exposure or ultraviolet light) and cod
liver oil are efficient in the treatment of tuberculosis (reviewed in Ref. 422). A well-known acknowledgement of
the success of such trials was Niels Ryberg Finsen’s Nobel Prize in Physiology or Medicine in 1903 for his contribution to the treatment of diseases, especially lupus
vulgaris (cutaneous tuberculosis), with concentrated
light radiation. Second, vitamin D deficiency is associated
with tuberculosis (563), and VDR variations confer
increased susceptibility to Mycobacterium tuberculosis
infection in humans (38, 563). Third, 1,25(OH)2D3 induces an antimicrobial activity against Mycobacterium
tubercolosis of cultured monocytes/macrophages (103,
442, 444, 476). Last, African Americans are known to
have increased susceptibility to Mycobacterium tuberculosis infection (204, 304), most likely because of the
lower level of vitamin D3 and cathelicidin D. Supplementation of the African American serum with 25(OH)D3 to
a physiological range restored TLR induction of cathelicidin mRNA (204, 304).
Remarkably, correlation between insufficient vitamin D
status and ulcerative colitis and Crohn’s disease was also
documented (204). More recent findings illustrate how
vitamin D deficiency may be a cause for these conditions.
Nod2 (Card15) gene, encoding an intracellular pattern
recognition receptor, has been identified as a direct target
gene of VDR (547). Because Crohn’s disease pathogenesis is associated with attenuated NOD2 (218, 389), this
study provides a molecular mechanism to explain the
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198, 269, 426 – 428). The key feature of endogenous
1,25(OH)2D3 production is the upregulation of enzymes
involved in the synthesis of 1,25 (OH)2D3. As we could
see previously, the inactive 25(OH)D3 is converted to
1,25(OH)2D3 by CYP27B enzyme. (Most likely this second hydroxylation is the limiting step in antigen presenting cells.) Interestingly, while the expression of CYP27B1
in the kidney are inhibited by many signals [e.g., calcium,
parathyroid hormone, phosphate, and 1,25(OH)2D3 itself (94, 143, 149, 199, 364, 416, 429, 526)], antigen
presenting cells seem to lack responsiveness to these inhibitory signals (7, 183, 199, 426). In contrast, CYP27B1
is upregulated in macrophages and/or DCs by various
maturation/activation stimuli, including IFN-␥, IL-2,
LPS, TLR2/1-activator, CL075, CD40 ligation, TNF-␣,
and polyI:C (6, 7, 147, 198, 304, 419, 426, 427, 507). In
some cases, responses of macrophages and DCs are different. For example, synthetic 19-kDa Mycobacterium
tuberculosis-derived lipopeptide upregulates CYP27B1
in monocytes and macrophages, but not in DCs (304).
Some agents, e.g., LPS, TLR2/1L, and CL075, are able to
induce the expression of both VDR and CYP27B1, leading
to elevated receptor and ligand levels simultaneously. The
inactivation of 1,25(OH)2D3 is carried out predominantly
by the CYP24A1 enzyme, which is a direct VDR target
gene.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
connection between vitamin D deficiency and the genetics
of Crohn’s disease. Another study demonstrated that impaired vitamin D leads to dysregulated colonic antimicrobial activity and impaired homeostasis of enteric bacteria (277). DNA array analysis of colon tissue also identified
many genes, including angiogenin-4, an antimicrobial
protein being consistently downregulated in vitamin Ddeficient mice providing a pivotal mechanism linking vitamin D status with inflammatory bowel disease in humans (277).
G. Therapeutic Considerations of
1,25(OH)2D3
Animal studies also demonstrated that vitamin D and its
analogs can prevent the development of various autoimmune diseases, including systemic lupus erythematosus, experimental allergic encephalomyelitis, collagen-induced arthritis, Lyme arthritis, inflammatory bowel disease, and autoimmune diabetes in NOD mice (reviewed in Ref. 326). To
some extent, they are also effective in the treatment of these
diseases. In addition, VDR agonists prolong allograft survival in a variety of experimental models supporting a further potential pharmacological application for this hormone or its analogs (9, 326).
Vitamin D deficiency is also among risk factors of tuberculosis infection (381). Apparently, vaccination and antibiotics are the most effective way of prevention and
treatment of tubercolosis, but vitamin D can also increase resistance to infection, especially in nonvaccinated
people (385, 422). Clinical trials of adjunctive vitamin D
768
IX. COMPLEXITY OF GENE REGULATION
BY NUCLEAR RECEPTORS: FROM
PATHWAYS TO NETWORKS
It appears that there are extensive interactions between nuclear receptor-regulated events and also other signaling and
transcription networks. A nice documentation of such interaction between TLR and nuclear receptor signaling was
provided by Glass and colleagues (388), who were able to
show that while the glucocorticoid receptor-mediated transcriptional repression takes place by the disruption of the
p65/IRF complex, PPAR␥ and LXR-mediated repression is
independent of this pathway.
Here we attempt to classify the various modes of interactions and illustrate these with examples we already detailed
above. Analyses of cell surface markers as well as functional
tests and gene expression profiling demonstrated that agonists for RXR, RAR, LXR, PPAR, and VDR regulate overlapping sets of genes and functions in macrophages and
DCs (508). This phenomenon is due to the fact that activation of nuclear receptors is resulted in parallel signaling and
crosstalk between these receptors (FIGURE 7). These observations suggest that instead of isolated pathways, one must
consider networks involving nuclear receptors, cofactors,
and enzymes that participate in the production of active
ligands. Others and also us could present evidence for this
parallel signaling and cross-communication between nuclear receptors, many of them take place in macrophages
and DCs.
Some examples are given here and are illustrated on FIGURE
We could identify four distinct modes of interactions. 1)
Many natural ligands can activate more then one nuclear
receptors, e.g., ATRA is a ligand for both RAR and PPAR␦,
while DHA can regulate both RXR and PPAR (116). RXR
agonists induce several pathways in parallel, because they
can regulate RXR homodimers and many permissive heterodimers, e.g., LXR:RXR and PPAR:RXR (508). The biological relevance of this redundancy is not clear. 2) One
nuclear receptor can serve as a sensor and be activated by
multiple ligands. For example, PPAR␥ is regulated by various modified fatty acids and prostanoids. 3) Some nuclear
receptors are primary targets of other nuclear receptors,
e.g., LXR␣ and PPAR␦ are regulated by PPAR␥ (77) and
VDR (130), respectively. 4) One receptor can modify the
activity of other nuclear receptors and transcription factors.
This is carried out by regulating the expression of co-factors, enzymes, and scavenger receptors and by antagonizing
other transcription factors. For example, RAR can induce
the expression of RIP140, which could influence RAR and
PPAR signaling (146, 558). A particularly intriguing example of the crosstalk is the regulation of endogenous ligand
7.
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It has been estimated that 1 billion people worldwide
have vitamin D deficiency or insufficiency [25(OH)D3
serum level below 50 nM] (204). Many aspects of vitamin D deficiency are discussed in details in a recent review (204). Rickets and osteomalacia are well known but
are rather extreme examples of the effects of vitamin D
deficiency. 1,25(OH)2D3 has a broad range of biological
activities, and it is not surprising that vitamin D insufficiency can raise the risk for various diseases and susceptibility for infections. Living at higher latitudes (where
UVB doses are lower) increases the risk of various types
of cancer. Furthermore, correlations have been found
between higher latitudes and risk of type 1 diabetes, multiple sclerosis, Crohn’s disease, hypertension, and cardiovascular disease (204). In parallel, vitamin D supplementation could reduce the risk for developing autoimmune
diseases, e.g., multiple sclerosis, rheumatoid arthritis,
and osteoarthritis, as well as of type I diabetes (204, 329,
337, 362). Although in many cases the correlation between D insufficiency and the risk for the disease is
clearly demonstrated, the exact mechanisms for vitamin
D effect and the target cell types are not defined.
therapy in active tuberculosis are reviewed in Reference
422.
NAGY ET AL.
production. There are multiple examples for such activity in
macrophages and DCs. For example, we have shown that
PPAR␥ can transform DCs to RA-producing cells providing
ligand for RARs (504), also the dual regulation of CYP27
by RAR and PPAR␥ leads to increased ligand production
for LXR (498). Nuclear receptors, e.g., GR, VDR, LXRs,
and PPARs, are described and considered as negative regulators of many inflammatory responses. A unique crosstalk
between these nuclear receptors and other transcription factors (e.g., NF-␬B, AP-1, and IRFs) has been documented in
the process of transrepression (162), suggesting that one
must investigate signaling pathways together to understand
the effects of nuclear receptors. Novel technologies (e.g.,
microarray, ChIP-chip, GRO-Seq, RNA-Seq, additional
new-generation sequencing technologies, etc.) revealed and
continue to reveal another level of complexity of transcriptional networks on the promoter/enhancer regions of genes.
These technologies are likely to be transformative in terms
of providing large genome scale datasets. For example,
C/EBPs were reported to bind to the vicinity of PPAR␥
response elements in adipocytes (282, 380). Recently, we
could show such an interaction exists between PPAR␥ and
the transcriptional mediator of IL-4 signaling STAT6 (497).
This interaction and the facilitating role of STAT6 for
PPAR␥ signaling provides a plausible explanation for the
enhanced receptor activity in IL-4-exposed alternatively activated macrophages and DCs. Further similar interactions
are expected to be uncovered by genome-wide localization
and profiling approaches.
As more and more such interactions are revealed, the interpretation and analysis of data require the implementation
of mathematical models. One can identify well-established
regulatory logic circuit elements such as autoregulation of
LXR expression in human cells (562), positive feedback
loop in the induction of the scavenger receptor CD36 by
PPAR␥, which leads to increased oxLDL uptake and further
activation of PPAR␥ or regulatory chains or cascades when
RAR facilitates PPAR␥ signaling and that in turn activates
LXR (77, 520) (FIGURE 7). Genome-wide analyses might
contribute to the identification of further interactions and
reveal the regulatory logic of lipid signaling via nuclear
receptors in these cell types. These analyses eventually will
lead to true system level understanding of these processes
especially if integrated to other transcriptional networks
such as NF-␬B, etc.
X. LIGAND PRODUCTION BY DENDRITIC
CELLS IS INVOLVED IN
DETERMINATION OF T-CELL HOMING
AND DEVELOPMENT
Although it is a key issue to determine how endogenous
ligands are produced for nuclear receptors in macrophages
and DCs, it is also conceivable that these cells themselves
may serve as sources of ligands for other cells of the immune
system, therefore contributing to paracrine nuclear receptor
ligand signaling.
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FIGURE 7. Distinct logic circuits can be identified among the various interactions of nuclear receptor
pathways in macrophages. A: “single input”: one ligand (L) can activate more than one RXR heterodimer
(NR1, NR2, and NR3). For example, docosahexaenoic acid (DHA) can regulate both RXR and PPAR.
B: “multiple input”: one nuclear receptor (NR) is activated by several agonists. For example, the relatively
large ligand-binding pocket of PPAR␥ can bind a broad range of natural and synthetic ligands. C: nuclear
receptors can regulate the transcription of their own (NR1) and other nuclear receptors (NR2-NR6).
“Autoregulation”: LXR␣ regulates its own transcription in human cells. VDR regulates the expression of
PPAR␦. “Regulatory chain”: RAR enhances PPAR␥ response and PPAR␥ turns on LXR␣ gene expression.
D: nuclear receptors can modify the activity of other nuclear receptors and transcription factors. Many
nuclear receptors, e.g., VDR, LXRs, and PPARs, are considered as negative regulators of other transcription factors (TF) such as NF-␬B and AP-1. PPAR␥ regulates the expression of CD36 scavenger
receptor (SR). Upregulation of CD36 leads to increased oxidized LDL uptake and PPAR␥ activation. The
level of endogenous ligands can be regulated by inducing enzymes involved in the ligand conversion. For
example, PPAR␥ can transform DCs to retinoic acid producing cells providing ligand for RAR. One receptor
could indirectly influence the activity of another nuclear receptor by regulating the expression of certain
cofactors. For example, RAR can induce the expression of RIP140, which could influence RAR and PPAR
signaling (NR1, NR2).
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
A. Retinoic Acid Production by DCs
It is intriguing which factors modulate the ATRA production capacity of DCs. It is possible that some antigen
presenting cells (CD103⫹ DCs) have an inherent capac-
770
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Emerging data suggested that various subsets of intestinal DCs can produce retinoic acid, more precisely ATRA,
and this locally generated compound shapes the intestinal immune response via a paracrine modulation of lymphocyte development/activation. First, Iwata et al. (228)
described that mesenteric lymph node (MLN) and Peyer
patch (PP) DCs, isolated from mouse intestine, are able to
produce ATRA in vitro (228). Consistent with this finding, these cells expressed several genes, which might be
responsible for ATRA production, for example, MLN
DCs expressed the transcript of alcohol dehydrogenase
III and Raldh2 (aldh1a2) (228). ATRA is the active form
of vitamin A, which is generated after two consecutive
oxidation steps from retinol (vitamin A). First, retinol is
oxidized to retinaldehyde (retinal) and then this compound is converted to ATRA. The first step is catalyzed
by alcohol dehydrogenases and/or short-chain dehydrogenases/reductases (some of them are called retinol dehydrogenases), and the second irreversible step is catalyzed
by retinaldehyde dehydrogenase (Raldhs) (129). It is still
controversial which enzyme activities catalyze in vivo
these reactions; however, genetic data indicated that, at
least during early embryonic development, Raldh2 enzyme has a pivotal role (379). It seems that Raldh2 also
had an important role for the production of DC-derived
ATRA. The CD103⫹ subset of PP and MLN murine DCs
highly expressed Raldh2, and these cells profoundly
stimulated regulatory T-cell (Treg) development. Moreover, RAR antagonist (LE540, LE135) efficiently
blocked Treg formation, suggesting that ATRA production was important for this step (97). Interestingly, a
follow-up study revealed that a similar CD103⫹ DC
population was detected in human mesenteric lymph
nodes, and these human cells might also produce ATRA
since the DC-dependent induction of gut homing receptors (CCR9 and ␣4␤7) on T cells was blocked with a
RAR antagonist (229). Gut-specific DC population is
rather heterogeneous, a macrophage-like DC subtype
(CD11c/CD11b double-positive cells) was isolated from
the lamina propria, which expressed Raldh2 and produced ATRA (527). Of note, intestinal macrophages
could also synthesize ATRA (121, 242); in addition, gutassociated stromal cells might also contribute to ATRA
production (187, 343). These findings demonstrated that
at least a few subsets of intestinal DCs can generate
ATRA, and this is a gut-specific propensity of the DCs.
However, a recent study described that a subset of migratory DCs derived from skin and lung was able to
produce ATRA and induce Treg development, suggesting
that ATRA-producing DCs are not restricted to the intestine (181).
ity to produce ATRA, more likely that the local environment instructs these cells to generate ATRA. Much effort
has been applied over the past few years to identify the
signaling pathways that modulate the ATRA production
capacity of DCs. Our global gene expression profile analysis suggested that human PPAR␥-instructed DCs generate ATRA. We found that several genes were upregulated, which participate in retinol/retinal oxidation
(504). More importantly, our liquid chromatographymass spectrometry analysis indicated that these PPAR␥
ligand-treated DCs produced ATRA ex vivo. There are
conflicting reports on the effects of PPAR␥ activators in
mouse DCs. Iwata and co-workers’ (578) analysis indicated that PPAR␥ ligand failed to induce RALDH2 expression in Flt3L-induced murine bone marrow-derived
DCs; however, PPAR␥ activation enhanced Treg generation through increased ATRA synthesis in murine splenic
DCs (215). It should be mentioned that our gene expression analysis revealed that besides the elevated expression of RALDH2, one of the retinol dehydrogenases
(RDH10) was also upregulated in PPAR␥ ligand-treated
DC. It is controversial whether the first or the second
oxidation step is the rate limiting for the in vivo ATRA
synthesis. Retinol conversion to retinal is catalyzed by
many enzymes (at least in vitro), suggesting that this step
has no role in the spatial or temporal regulation of ATRA
synthesis (129). However, this notion has been challenged recently: RDH10 plays a critical role in embryonic
ATRA synthesis, and loss of RDH10 function disrupts
ATRA production during embryonic development (453).
Consistent with this notion, it was also documented that
a special gut-specific human antigen presenting cell (having shared DC and macrophage markers) also had an
elevated expression of RDH10, suggesting that this enzyme activity might contribute to the ATRA generation
at least in human cells (242). Our data also indicated that
human monocyte-derived DCs had a relatively high expression of Raldh2. Importantly, this in vitro DC differentiation is driven by IL-4 and GM-CSF cytokines; hence,
it is possible that these cytokines might participate in the
regulation of Raldh2 expression. Indeed, IL-4 had a positive effect on the expression of Raldh2 in mesenteric
lymph node DCs, and IL-4 receptor-deficient cells had a
reduced expression of Raldh2 (134). Additionally, GMCSF also stimulated Raldh2 expression both in bone
marrow-derived and splenic DCs, and this induction was
enhanced in the presence of IL-4. Moreover, GM-CSF
receptor-deficient animals showed an impaired intestinal
ATRA production (578). Notably, in this report, SPF
pathogen-free condition was applied since it turned out
that TLR activators also enhanced RA production (578).
In line with this finding, TLR2 ligand (zymosan) profoundly promoted the Raldh2 expression in splenic DCs
(320). In addition, this TLR2-dependent Raldh2 induction was blocked with ERK kinase or syk kinase inhibitors, suggesting that these intracellular signaling path-
NAGY ET AL.
B. Modulation of Intestinal Immunity
by DCs Via Production of
Retinoic Acid
One of the major breakthroughs in DC biology was the
deciphering of molecular mechanisms of gut-specific lymphocyte imprinting and oral tolerance (FIGURE 8). Several
lines of evidence suggested that DC-derived ATRA signaling has a central role in these processes. It was preciously
observed that expression of the gut-homing receptors
(␣4␤7 integrin and CCR9) was essential for the preferential
homing of T cells to the intestine (185, 494). Iwata and
co-workers discovered that ATRA enhanced the expression
of these gut homing receptors (␣4␤7 and CCR9) in T lymphocytes. Moreover, they found that T cells that were
primed in the presence of ATRA showed a preferential gut
homing specificity (228). Notably, DC-derived ATRA was
FIGURE 8. The role of all-trans-retinoic acid and 1␣,25-dihydroxyvitamin D3 in T-cell homing and lymphocyte
specification. A: schematic representation of the interaction between an activated DC and a lymphocyte.
Nuclear receptor ligands are involved in the polarization and homing of lymphocytes. B: contribution of
all-trans-retinoic acid (ATRA) and 1␣,25-dihydroxyvitamin D3 [1,25(OH)2D3] to the development of gut or
epidermis homing phenotype of T cells, respectively. C: role and contribution of ATRA to the development of
regulatory T cells and IgA-producing B cells.
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ways might participate in the positive regulation of this
key enzyme of RA synthesis. Of note, intestinal DCs and
macrophages derived from ␤-catenin null mice expressed
much lower amounts of Raldh1 and -2 transcripts and
proteins compared with wild-type cells. These data suggested that the ␤-catenin pathway directly or indirectly
modulates the ATRA-producing capacity of the intestinal
antigen-presenting cells (321). Interestingly, ATRA itself
could directly induce Raldh2 in DCs, suggesting that
ATRA enhances its own synthesis (344). Finally, a negative regulator of the ATRA synthesis was also identified:
prostaglandin E2 enhanced the expression of the inducible cAMP early repressor, which appears to directly inhibit RALDH expression in DCs (488). Taken together,
these results demonstrated that at least in vitro several
signaling pathways contribute to the regulation of DCspecific ATRA synthesis.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
also important for gut tropism in B cells (349). Numerous
reports confirmed the ATRA-dependent induction of these
receptors on T cells; however, it is still poorly characterized
the ATRA-mediated regulation of ␣4␤7 and CCR9. CCR9
expression seemed to be more dependent on ATRA than
␣4␤7. Moreover, a functional cooperation was recently described between NFATc2 and the RAR:RXR heterodimer
complex on the promoter region of the mouse Ccr9 gene,
suggesting that ATRA directly modulates the expression of
CCR9 (390).
It seems that the effect of ATRA on T-cell regulation is more
complex. Although it enhances TGF-␤-mediated Foxp3⫹ T
cell development, ATRA represses IL-10 production of
these cells. Consistently vitamin A-deficient mice have enhanced IL-10-producing iTreg cells (328). Unexpectedly,
ATRA was required to provoke a pro-inflammatory T-cell
response to infection and mucosal vaccination. It seems that
T cell specific RAR␣ was the critical receptor of these effects: inhibition of the RAR signaling and deficiency in
RAR␣ resulted in a cell-autonomous CD4⫹ T cell activation defect (184). In addition, ATRA can elicit a proinflammatory phenotype in intestinal DCs to dietary antigens in a
murine model of celiac disease. It was observed that ATRA
synergizes with IL-15 to promote the breakdown of gluten
tolerance and potentiate production of IL-12 and IL-23 by
mucosal DCs (122). These unexpected results indicated that
772
C. Connection Between 1,25(OH)2D3
Released by DCs and Epidermal
Lymphocyte Homing
Similarly to ATRA, 1,25(OH)2D3 was also implicated in
ligand-induced lymphocyte trafficking (FIGURE 8). CCR10
is a chemokine receptor, expressed by 1% of CD8⫹ T cells
and 5% of CD4⫹ T cells (474). Its ligand, CCL27, is a
chemoattractant, selectively expressed by keratinocytes of
the epidermis. This chemokine is thought to mediate and/or
influence the epidermotropism of CCR10⫹ T cells from
dermis, the retention of T cells in or near the epidermis, and
the homing of cells from the blood into the vascular dermis
(210, 351, 432, 474). The expression of CCR10 in human T
cells and the migration of T cells toward CCL27 were significantly induced in the presence of 1,25(OH)2D3, especially when added together with IL-12 (474). Further experiments showed that naive but not memory or previously
activated T cells required IL-12 for efficient 1,25(OH)2D3mediated induction of CCR10. In the promoter of CCR10,
a DR3-type VDRE has been identified, suggesting a direct
ligand-dependent regulation (474). 1,25(OH)2D3 alone or
with IL-12 upregulate CCR10 in mouse T cells as well,
albeit not as efficiently as in human T cells. The concentrations found in normal serum were ineffective to induce the
CCR10 level of T cells. Importantly, monocyte-derived
DCs themselves and T cell-DC cocultures could convert
vitamin D3 to 1,25(OH)2D3, because both hydroxylation
steps could be accomplished by DCs (see above). It should
be noted that T cells could convert only 25(OH)D3 to
1,25(OH)2D3. These results do not exclude the possibility
that other cell types, e.g., keratinocytes, could also process
vitamin D to 1,25(OH)2D3 in the skin. In agreement with
these results, 25(OH)D3 and vitamin D itself could induce
CCR10 expression on T cells interacting with antigen presenting DCs. Sigmundsdottir et al. (474) could document
the ability of skin-associated DCs to metabolize the sunlight-induced vitamin D using DCs obtained by cannulating
an afferent lymph vessel draining site of chronic skin inflammation in sheep. The survey on the effect of
1,25(OH)2D3 on other molecules important for skin homing helps to address which aspect of T-cell migration is
affected by 1,25(OH)2D3. Migration of effector and memory T cells relies on the expression of ligands for E- and
P-selectin and CCR4 and CCR10 (348, 350). 1,25(OH)2D3
failed to induce the expression of CCR4 and other skin
homing-associated chemokine receptors CCR6 and CCR8
(348, 350). Moreover, 1,25(OH)2D3 blocks the upregulation of ligands of E-selectin and the expression of fucosyl-
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In addition to T-cell tropism, DC-derived ATRA also
facilitates the B-cell IgA secretion along with the commensural flora and TSLP. Moreover, vitamin A-deficient
mice lacked IgA-secreting cells, suggesting the in vivo
relevance of this regulation (349). After the identification
of the gut homing tropism of retinoid signaling, it was
found that ATRA also participated in the regulation of
oral tolerance. Oral tolerance is the immunologic mechanism by which the gut immune system maintains unresponsiveness to antigens upon enteral uptake. Several
lines of evidence suggested that inducible regulatory T
cells (iTregs) have an important role in the maintenance
of gut immune tolerance (105). Remarkably, intestinal
DC-derived ATRA signaling elicited iTreg development
via a synergy with TGF-␤ (355). This finding was confirmed by others, and an ATRA-producing DC subtype
(CD103⫹ cells) was identified that modulates these processes (42, 97, 492). The mechanism of ATRA-dependent
iTreg regulation is still poorly characterized; however,
one report suggested that RAR␣ activation directly induced histone acetylation in the promoter of FoxP3 (a
master regulator of iTreg development) (105), hence activating this key gene (245). We have to note that it is still
unclear whether ATRA directly stimulates iTreg differentiation or this is an indirect effect; one report suggested
that ATRA indirectly regulates this process through the
negative regulation of CD44 high T cells (201, 356) (FIGURE 8).
in a stressed intestinal environment, ATRA can act as an
adjuvant that promotes rather than represses inflammatory
responses. Taken together, these results suggested that DCderived ATRA has a complex role on shaping lymphocyte
activation and polarization in gut-associated lymphoid tissue.
NAGY ET AL.
transferase-VII, an enzyme essential for the synthesis
of selectin ligands (316, 350, 474, 574). Remarkably,
1,25(OH)2D3 inhibited T-cell homing to the inflamed skin
(574). These data collectively suggest that 1,25(OH)2D3
does not mediate T-cell recruitment from the blood. Instead, 1,25(OH)2D3 may act on T cells directly in the skin,
after T cells infiltrated the dermis, inducing CCR10 to generate a T-cell attraction signal toward (and/or retention in)
the epidermis.
XI. CONCLUSIONS AND PERSPECTIVES
From a molecular endocrinologist, “receptorologist” point
of view, simply the large-scale identification of primary and
secondary nuclear receptor targets proved to be very useful.
At the same time, the relatively easy accessibility and availability of these cell types from both humans and mice makes
these cells ideal for ex vivo culture and study. In particular,
the possibility of analyzing multiple interacting pathways
simultaneously in normal human or murine homogeneous
cell populations is a unique opportunity. For example, issues such as the nature of RXR activation in the context of
several heterodimers could be addressed. The identified target genes and pathways then could and should be verified
and followed up in genetic models in vivo, which is a more
tedious task, and these can contribute to a better understanding of receptor activity, interaction, and networking.
Also, the molecular details of target gene activation and
repression can be dissected at a genomic scale.
From an immunologist point of view, the introduction of
nuclear receptors as modulators of immune cell differentiation and function provides an approachable system to
probe the plasticity of macrophages and DCs and also to
uncover the regulatory logic of immune cell differentiation,
not in small part thanks to the availability of synthetic ligands. For example, we find it remarkable that simply applying lipids on DCs one can generate a range of activities
leading to various T-cell subpopulations and also changing
their relative amounts (FIGURE 5). These experiments also
showed that activation of nuclear receptor pathways have
specific effects rather than general peiotropic ones on the
differentiation and function of immune cells.
A key outstanding issue is to determine to what degree these
pathways are utilized in vivo and how endogenous ligand
From a more clinical and practical point of view, the identification and characterization of nuclear receptor-mediated
pathways in these key immune cells are likely to contribute
to a better understanding of disease mechanisms and potentially opening the door for the development for therapeutic
approaches in chronic inflammatory diseases and autoimmunity. However, there is much more to do: more emphasis
should be put on the systems level analyses, animal models
in which genetic elimination of a particular receptor is possible in a given cell type at will; more thorough lipidomics to
determine which are the active metabolic pathways and also
more human clinical studies are required to avoid or bypass
species specific phenomena and to convince even skeptics
about the viability of such approaches and ease the translation of key findings to the clinic.
ACKNOWLEDGMENTS
The authors are indebted to Dr. Eva Rajnavolgyi and members of the Nagy laboratory for comments on the manuscript and Csaba Antal for artwork.
Present addresses: A. Szanto, Howard Hughes Medical Institute, Dept. of Molecular Biology, Massachusetts General
Hospital, Dept. of Genetics, Harvard Medical School, 185
Cambridge St., Boston, MA 02114; L. Széles, Dept. of Pathology and Immunology, Faculty of Medicine, University
of Geneva, 1 Rue Michel-Servet, 1211 Geneva, Switzerland.
Address for reprint requests and other correspondence: L.
Nagy, Dept. of Biochemistry and Molecular Biology, Univ.
of Debrecen, Medical and Health Science Center, Egyetem
tér 1, Debrecen, Hungary H-4010 (e-mail: nagyl@med.
unideb.hu).
GRANTS
L. Nagy is an International Scholar of the Howard
Hughes Medical Institute and holds a Wellcome Trust
Senior Research Fellowship in Biomedical Sciences. He is
also supported by a grant from the Hungarian Science
Research Fund (OTKA NK72730), TAMOP-4.2.2/08/1,
and TAMOP-4.2.1/B-090/1/KONV-2010-0007 implemented through the New Hungary Development Plan
co-financed by the European Social Fund and the European Regional Development Fund.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the authors.
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The remarkable versatility and plasticity of macrophages
and DCs makes them an ideal target for studying the activity of lipid-activated transcription factors, nuclear receptors. The last 15 years have brought a significant advance in
this field. This was not in small part due to the availability of
gene expression profiling and other genome-wide approaches. Now the contribution of retinoid, fatty acid, cholesterol, and prostanoid compounds via nuclear receptors
on cell type specification and differentiation has been accepted by the immunology community.
production is regulated. Also, it should be explored how
these pathways interact with each other and with key inflammatory transcriptional responses such as NF-␬B, AP1,
or STATs.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
REFERENCES
19. Andersson S, Davis DL, Dahlback H, Jornvall H, Russell DW. Cloning, structure, and
expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid
biosynthetic enzyme. J Biol Chem 264: 8222– 8229, 1989.
1. A IUPAC IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of vitamin D recommendations 1981. Mol Cell Biochem 49: 177–181, 1982.
2. Adachi M, Kurotani R, Morimura K, Shah Y, Sanford M, Madison BB, Gumucio DL,
Marin HE, Peters JM, Young HA, Gonzalez FJ. Peroxisome proliferator activated
receptor gamma in colonic epithelial cells protects against experimental inflammatory
bowel disease. Gut 55: 1104 –1113, 2006.
3. Adams J, Kiss E, Arroyo AB, Bonrouhi M, Sun Q, Li Z, Gretz N, Schnitger A, Zouboulis
CC, Wiesel M, Wagner J, Nelson PJ, Grone HJ. 13-Cis retinoic acid inhibits development and progression of chronic allograft nephropathy. Am J Pathol 167: 285–298,
2005.
4. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the
regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 4: 80 –90,
2008.
6. Adams JS, Modlin RL, Diz MM, Barnes PF. Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid.
J Clin Endocrinol Metab 69: 457– 460, 1989.
7. Adams JS, Ren SY, Arbelle JE, Horiuchi N, Gray RW, Clemens TL, Shany S. Regulated
production and intracrine action of 1,25-dihydroxyvitamin D3 in the chick myelomonocytic cell line HD-11. Endocrinology 134: 2567–2573, 1994.
8. Adams JS, Singer FR, Gacad MA, Sharma OP, Hayes MJ, Vouros P, Holick MF. Isolation
and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin Endocrinol Metab 60: 960 –966, 1985.
9. Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine
system. Nat Clin Pract Rheumatol 4: 404 – 412, 2008.
10. Adorini L, Penna G, Giarratana N, Roncari A, Amuchastegui S, Daniel KC, Uskokovic
M. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol 89 –90: 437– 441, 2004.
11. Agostini M, Schoenmakers E, Mitchell C, Szatmari I, Savage D, Smith A, Rajanayagam
O, Semple R, Luan J, Bath L, Zalin A, Labib M, Kumar S, Simpson H, Blom D, Marais
D, Schwabe J, Barroso I, Trembath R, Wareham N, Nagy L, Gurnell M, O’Rahilly S,
Chatterjee K. Non-DNA binding, dominant-negative, and human PPARgamma mutations cause lipodystrophic insulin resistance. Cell Metab 4: 303–311, 2006.
12. Agura ED, Howard M, Collins SJ. Identification and sequence analysis of the promoter
for the leukocyte integrin beta-subunit (CD18): a retinoic acid-inducible gene. Blood
79: 602– 609, 1992.
13. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 4: 499 –511, 2004.
14. Akiyama TE, Sakai S, Lambert G, Nicol CJ, Matsusue K, Pimprale S, Lee YH, Ricote M,
Glass CK, Brewer HB Jr, Gonzalez FJ. Conditional disruption of the peroxisome
proliferator-activated receptor gamma gene in mice results in lowered expression of
ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. Mol Cell
Biol 22: 2607–2619, 2002.
15. Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N.
Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36,
cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188: 1359 –1368, 1998.
16. Aldridge JR Jr, Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, Brown SA,
Doherty PC, Webster RG, Thomas PG. TNF/iNOS-producing dendritic cells are the
necessary evil of lethal influenza virus infection. Proc Natl Acad Sci USA 106: 5306 –
5311, 2009.
17. Alleva DG, Johnson EB, Lio FM, Boehme SA, Conlon PJ, Crowe PD. Regulation of
murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for
peroxisome proliferator-activated receptor-gamma: counter-regulatory activity by
IFN-gamma. J Leukoc Biol 71: 677– 685, 2002.
18. Anderson KL, Perkin H, Surh CD, Venturini S, Maki RA, Torbett BE. Transcription
factor PU.1 is necessary for development of thymic and myeloid progenitor-derived
dendritic cells. J Immunol 164: 1855–1861, 2000.
774
21. Angeli V, Hammad H, Staels B, Capron M, Lambrecht BN, Trottein F. Peroxisome
proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response. J Immunol 170: 5295–5301, 2003.
22. Angeli V, Llodra J, Rong JX, Satoh K, Ishii S, Shimizu T, Fisher EA, Randolph GJ.
Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell
mobilization. Immunity 21: 561–574, 2004.
23. Appel S, Mirakaj V, Bringmann A, Weck MM, Grunebach F, Brossart P. PPAR-gamma
agonists inhibit toll-like receptor mediated activation of dendritic cells via the MAP
kinase and NF-kappaB pathways. Blood 2005.
24. Auffray C, Fogg DK, Narni-Mancinelli E, Senechal B, Trouillet C, Saederup N, Leemput J, Bigot K, Campisi L, Abitbol M, Molina T, Charo I, Hume DA, Cumano A, Lauvau
G, Geissmann F. CX3CR1⫹ CD115⫹ CD135⫹ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J Exp Med 206:
595– 606, 2009.
25. Babaev VR, Yancey PG, Ryzhov SV, Kon V, Breyer MD, Magnuson MA, Fazio S, Linton
MF. Conditional knockout of macrophage PPARgamma increases atherosclerosis in
C57BL/6 and low-density lipoprotein receptor-deficient mice. Arterioscler Thromb
Vasc Biol 25: 1647–1653, 2005.
26. Babiker A, Andersson O, Lindblom D, van der Linden J, Wiklund B, Lutjohann D,
Diczfalusy U, Bjorkhem I. Elimination of cholesterol as cholestenoic acid in human
lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of
pulmonary origin. J Lipid Res 40: 1417–1425, 1999.
27. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike
JW, Shine J, O’Malley BW. Cloning and expression of full-length cDNA encoding
human vitamin D receptor. Proc Natl Acad Sci USA 85: 3294 –3298, 1988.
28. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 392:
245–252, 1998.
29. Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM. Increased p85/55/50 expression
and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54: 2351–2359, 2005.
30. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans
RM. PPAR gamma is required for placental, cardiac, adipose tissue development. Mol
Cell 4: 585–595, 1999.
31. Barlic J, Zhang Y, Foley JF, Murphy PM. Oxidized lipid-driven chemokine receptor
switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary
artery smooth muscle cells through a peroxisome proliferator-activated receptor
gamma-dependent pathway. Circulation 114: 807– 819, 2006.
32. Barton AE, Bunce CM, Stockley RA, Harrison P, Brown G. 1 alpha,25-Dihydroxyvitamin D3 promotes monocytopoiesis and suppresses granulocytopoiesis in cultures of
normal human myeloid blast cells. J Leukoc Biol 56: 124 –132, 1994.
33. Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA. Synthesis
and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid. J Med Chem 39: 3556 –3563, 1996.
34. Becker S, Daniel EG. Antagonistic and additive effects of IL-4 and interferon-gamma
on human monocytes and macrophages: effects on Fc receptors, HLA-D antigens,
and superoxide production. Cell Immunol 129: 351–362, 1990.
35. Bedford PA, Knight SC. The effect of retinoids on dendritic cell function. Clin Exp
Immunol 75: 481– 486, 1989.
36. Behar SM, Porcelli SA. CD1-restricted T cells in host defense to infectious diseases.
Curr Top Microbiol Immunol 314: 215–250, 2007.
37. Behre G, Whitmarsh AJ, Coghlan MP, Hoang T, Carpenter CL, Zhang DE, Davis RJ,
Tenen DG. c-Jun is a JNK-independent coactivator of the PU.1 transcription factor. J
Biol Chem 274: 4939 – 4946, 1999.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
5. Adams JS, Liu PT, Chun R, Modlin RL, Hewison M. Vitamin D in defense of the human
immune response. Ann NY Acad Sci 1117: 94 –105, 2007.
20. Angeli V, Faveeuw C, Roye O, Fontaine J, Teissier E, Capron A, Wolowczuk I, Capron
M, Trottein F. Role of the parasite-derived prostaglandin D2 in the inhibition of
epidermal Langerhans cell migration during schistosomiasis infection. J Exp Med 193:
1135–1147, 2001.
NAGY ET AL.
38. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV.
Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the
vitamin D receptor gene. J Infect Dis 179: 721–724, 1999.
57. Brun RP, Tontonoz P, Forman BM, Ellis R, Chen J, Evans RM, Spiegelman BM. Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev 10: 974 –984,
1996.
39. Benoit G, Altucci L, Flexor M, Ruchaud S, Lillehaug J, Raffelsberger W, Gronemeyer H,
Lanotte M. RAR-independent RXR signaling induces t(15;17) leukemia cell maturation. EMBO J 18: 7011–7018, 1999.
58. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L,
Greene GL, Gustafsson JA, Carlquist M. Molecular basis of agonism and antagonism in
the oestrogen receptor. Nature 389: 753–758, 1997.
40. Benoit GR, Flexor M, Besancon F, Altucci L, Rossin A, Hillion J, Balajthy Z, Legres L,
Segal-Bendirdjian E, Gronemeyer H, Lanotte M. Autonomous rexinoid death signaling
is suppressed by converging signaling pathways in immature leukemia cells. Mol Endocrinol 15: 1154 –1169, 2001.
59. Budhu AS, Noy N. Direct channeling of retinoic acid between cellular retinoic acidbinding protein II and retinoic acid receptor sensitizes mammary carcinoma cells to
retinoic acid-induced growth arrest. Mol Cell Biol 22: 2632–2641, 2002.
41. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454: 470 – 477, 2008.
42. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates
enhanced T reg cell growth, differentiation, gut homing in the face of high levels of
co-stimulation. J Exp Med 204: 1765–1774, 2007.
44. Bhalla AK, Amento EP, Krane SM. Differential effects of 1,25-dihydroxyvitamin D3 on
human lymphocytes and monocyte/macrophages: inhibition of interleukin-2 and augmentation of interleukin-1 production. Cell Immunol 98: 311–322, 1986.
45. Bhatia M, Kirkland JB, Meckling-Gill KA. M-CSF and 1,25 dihydroxy vitamin D3 synergize with 12-O-tetradecanoylphorbol-13-acetate to induce macrophage differentiation in acute promyelocytic leukemia NB4 cells. Leukemia 8: 1744 –1749, 1994.
46. Bjorkhem I, Andersson O, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, Lund E. Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination
of cholesterol from human macrophages. Proc Natl Acad Sci USA 91: 8592– 8596,
1994.
47. Bjorkhem I, Leitersdorf E. Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans. Trends Endocrinol Metab 11: 180 –183, 2000.
48. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W,
Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K,
Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette
transporter 1 is mutated in Tangier disease. Nat Genet 22: 347–351, 1999.
49. Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM,
Davies JA, Heyman RA. Design and synthesis of potent retinoid X receptor selective
ligands that induce apoptosis in leukemia cells. J Med Chem 38: 3146 –3155, 1995.
50. Bonder CS, Dickensheets HL, Finlay-Jones JJ, Donnelly RP, Hart PH. Involvement of
the IL-2 receptor gamma-chain (gammac) in the control by IL-4 of human monocyte
and macrophage proinflammatory mediator production. J Immunol 160: 4048 – 4056,
1998.
51. Botling J, Oberg F, Torma H, Tuohimaa P, Blauer M, Nilsson K. Vitamin D3- and
retinoic acid-induced monocytic differentiation: interactions between the endogenous vitamin D3 receptor, retinoic acid receptors, and retinoid X receptors in U-937
cells. Cell Growth Differ 7: 1239 –1249, 1996.
52. Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude
B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G. PPARgamma activation primes
human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6: 137–143, 2007.
53. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer
C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K,
Koop B, Pimstone S, Kastelein JJ, Hayden MR. Mutations in ABC1 in Tangier disease
and familial high-density lipoprotein deficiency. Nat Genet 22: 336 –345, 1999.
54. Brown G, Bunce CM, Rowlands DC, Williams GR. All-trans retinoic acid and 1 alpha,25-dihydroxyvitamin D3 co-operate to promote differentiation of the human
promyeloid leukemia cell line HL60 to monocytes. Leukemia 8: 806 – 815, 1994.
61. Burmester JK, Maeda N, DeLuca HF. Isolation and expression of rat 1,25-dihydroxyvitamin D3 receptor cDNA. Proc Natl Acad Sci USA 85: 1005–1009, 1988.
62. Burmester JK, Wiese RJ, Maeda N, DeLuca HF. Structure and regulation of the rat
1,25-dihydroxyvitamin D3 receptor. Proc Natl Acad Sci USA 85: 9499 –9502, 1988.
63. Bush TS, St Coeur M, Resendes KK, Rosmarin AG. GA-binding protein (GABP) and
Sp1 are required, along with retinoid receptors, to mediate retinoic acid responsiveness of CD18 (beta 2 leukocyte integrin): a novel mechanism of transcriptional regulation in myeloid cells. Blood 101: 311–317, 2003.
64. Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic
enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem
266: 7779 –7783, 1991.
65. Cali JJ, Russell DW. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis. J Biol Chem 266: 7774 –7778, 1991.
66. Calleja C, Messaddeq N, Chapellier B, Yang H, Krezel W, Li M, Metzger D, Mascrez
B, Ohta K, Kagechika H, Endo Y, Mark M, Ghyselinck NB, Chambon P. Genetic and
pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in
mouse epidermis keratinocytes. Genes Dev 20: 1525–1538, 2006.
67. Cao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H,
Ryan TP, Liang Y, Eacho PI, Jiang XC. Phospholipid transfer protein is regulated by
liver X receptors in vivo. J Biol Chem 277: 39561–39565, 2002.
68. Carbone R, Botrugno OA, Ronzoni S, Insinga A, Di Croce L, Pelicci PG, Minucci S.
Recruitment of the histone methyltransferase SUV39H1 and its role in the oncogenic
properties of the leukemia-associated PML-retinoic acid receptor fusion protein. Mol
Cell Biol 26: 1288 –1296, 2006.
69. Carrasco YR, Batista FD. B cells acquire particulate antigen in a macrophage-rich area
at the boundary between the follicle and the subcapsular sinus of the lymph node.
Immunity 27: 160 –171, 2007.
70. Castrillo A, Diaz-Guerra MJ, Hortelano S, Martin-Sanz P, Bosca L. Inhibition of IkappaB kinase and IkappaB phosphorylation by 15-deoxy-Delta(12,14)-prostaglandin J(2)
in activated murine macrophages. Mol Cell Biol 20: 1692–1698, 2000.
71. Castrillo A, Joseph SB, Marathe C, Mangelsdorf DJ, Tontonoz P. Liver X receptordependent repression of matrix metalloproteinase-9 expression in macrophages. J
Biol Chem 278: 10443–10449, 2003.
72. Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, Tontonoz P.
Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral
antagonism of cholesterol metabolism. Mol Cell 12: 805– 816, 2003.
73. Castrillo A, Tontonoz P. Nuclear receptors in macrophage biology: at the crossroads
of lipid metabolism and inflammation. Annu Rev Cell Dev Biol 20: 455– 480, 2004.
74. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 10:
940 –954, 1996.
75. Chang MD, Pollard JW, Khalili H, Goyert SM, Diamond B. Mouse placental macrophages have a decreased ability to present antigen. Proc Natl Acad Sci USA 90: 462–
466, 1993.
55. Brumbaugh PF, Haussler MR. 1Alpha,25-dihydroxyvitamin D3 receptor: competitive
binding of vitamin D analogs. Life Sci 13: 1737–1746, 1973.
76. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent
and independent effects on macrophage-gene expression in lipid metabolism and
inflammation. Nat Med 7: 48 –52, 2001.
56. Brumbaugh PF, Haussler MR. Nuclear and cytoplasmic receptors for 1,25-dihydroxycholecalciferol in intestinal mucosa. Biochem Biophys Res Commun 51: 74 – 80, 1973.
77. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L,
Edwards PA, Curtiss LK, Evans RM, Tontonoz P. A PPAR gamma-LXR-ABCA1 path-
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
775
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
43. Berer A, Stockl J, Majdic O, Wagner T, Kollars M, Lechner K, Geissler K, Oehler L.
1,25-Dihydroxyvitamin D(3) inhibits dendritic cell differentiation and maturation in
vitro. Exp Hematol 28: 575–583, 2000.
60. Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG. RXR alpha, a promiscuous partner of
retinoic acid and thyroid hormone receptors. EMBO J 11: 1409 –1418, 1992.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
way in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:
161–171, 2001.
78. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology:
opening the X-files. Science 294: 1866 –1870, 2001.
79. Chen KS, DeLuca HF. Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24hydroxylase gene promoter and identification of two vitamin D-responsive elements.
Biochim Biophys Acta 1263: 1–9, 1995.
80. Chen M, Beaven S, Tontonoz P. Identification and characterization of two alternatively spliced transcript variants of human liver X receptor alpha. J Lipid Res 46:
2570 –2579, 2005.
81. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25dihydroxyvitamin D3 on human B cell differentiation. J Immunol 179: 1634 –1647,
2007.
83. Chen Z, Ishibashi S, Perrey S, Osuga J, Gotoda T, Kitamine T, Tamura Y, Okazaki H,
Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N.
Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic
effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 21: 372–377,
2001.
84. Chen ZP, Iyer J, Bourguet W, Held P, Mioskowski C, Lebeau L, Noy N, Chambon P,
Gronemeyer H. Ligand- and DNA-induced dissociation of RXR tetramers. J Mol Biol
275: 55– 65, 1998.
85. Chen ZX, Xue YQ, Zhang R, Tao RF, Xia XM, Li C, Wang W, Zu WY, Yao XZ, Ling
BJ. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 78: 1413–1419, 1991.
86. Cheung DL, Hart PH, Vitti GF, Whitty GA, Hamilton JA. Contrasting effects of interferon-gamma and interleukin-4 on the interleukin-6 activity of stimulated human
monocytes. Immunology 71: 70 –75, 1990.
87. Chih DY, Chumakov AM, Park DJ, Silla AG, Koeffler HP. Modulation of mRNA
expression of a novel human myeloid-selective CCAAT/enhancer binding protein
gene (C/EBP epsilon). Blood 90: 2987–2994, 1997.
88. Chisholm JW, Hong J, Mills SA, Lawn RM. The LXR ligand T0901317 induces severe
lipogenesis in the db/db diabetic mouse. J Lipid Res 44: 2039 –2048, 2003.
89. Chung SW, Kang BY, Kim SH, Pak YK, Cho D, Trinchieri G, Kim TS. Oxidized low
density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated
mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J Biol Chem 275: 32681–32687,
2000.
90. Clohisy DR, Bar-Shavit Z, Chappel JC, Teitelbaum SL. 1,25-Dihydroxyvitamin D3
modulates bone marrow macrophage precursor proliferation and differentiation. Upregulation of the mannose receptor. J Biol Chem 262: 15922–15929, 1987.
91. Cohen MS, Mesler DE, Snipes RG, Gray TK. 1,25-Dihydroxyvitamin D3 activates
secretion of hydrogen peroxide by human monocytes. J Immunol 136: 1049 –1053,
1986.
92. Collins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ,
Wilson JG, Tippin TK, Binz JG, Plunket KD, Morgan DG, Beaudet EJ, Whitney KD,
Kliewer SA, Willson TM. Identification of a nonsteroidal liver X receptor agonist
through parallel array synthesis of tertiary amines. J Med Chem 45: 1963–1966, 2002.
98. Costet P, Lalanne F, Gerbod-Giannone MC, Molina JR, Fu X, Lund EG, Gudas LJ, Tall
AR. Retinoic acid receptor-mediated induction of ABCA1 in macrophages. Mol Cell
Biol 23: 7756 –7766, 2003.
99. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the ABC1
promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275: 28240 –28245,
2000.
100. Coutant F, Agaugue S, Perrin-Cocon L, Andre P, Lotteau V. Sensing environmental
lipids by dendritic cell modulates its function. J Immunol 172: 54 – 60, 2004.
101. Coutant F, Perrin-Cocon L, Agaugue S, Delair T, Andre P, Lotteau V. Mature dendritic
cell generation promoted by lysophosphatidylcholine. J Immunol 169: 1688 –1695,
2002.
102. Crisby M, Nilsson J, Kostulas V, Bjorkhem I, Diczfalusy U. Localization of sterol
27-hydroxylase immuno-reactivity in human atherosclerotic plaques. Biochim Biophys
Acta 1344: 278 –285, 1997.
103. Crowle AJ, Ross EJ, May MH. Inhibition by 1,25(OH)2-vitamin D3 of the multiplication
of virulent tubercle bacilli in cultured human macrophages. Infect Immun 55: 2945–
2950, 1987.
104. Cua DJ, Stohlman SA. In vivo effects of T helper cell type 2 cytokines on macrophage
antigen-presenting cell induction of T helper subsets. J Immunol 159: 5834 –5840,
1997.
105. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3⫹ regulatory T cells:
more of the same or a division of labor? Immunity 30: 626 – 635, 2009.
106. D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia F,
Panina-Bordignon P. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3 involvement of NF-kappaB downregulation in transcriptional repression of the p40
gene. J Clin Invest 101: 252–262, 1998.
107. Dahl R, Walsh JC, Lancki D, Laslo P, Iyer SR, Singh H, Simon MC. Regulation of
macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte
colony-stimulating factor. Nat Immunol 4: 1029 –1036, 2003.
108. Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA. Multiple defects
of immune cell function in mice with disrupted interferon-gamma genes. Science 259:
1739 –1742, 1993.
109. Darmanin S, Chen J, Zhao S, Cui H, Shirkoohi R, Kubo N, Kuge Y, Tamaki N, Nakagawa K, Hamada J, Moriuchi T, Kobayashi M. All-trans retinoic acid enhances murine
dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors. J Immunol 179: 4616 – 4625, 2007.
110. Davies SS, Pontsler AV, Marathe GK, Harrison KA, Murphy RC, Hinshaw JC, Prestwich GD, Hilaire AS, Prescott SM, Zimmerman GA, McIntyre TM. Oxidized alkyl
phospholipids are specific, high affinity peroxisome proliferator-activated receptor
gamma ligands and agonists. J Biol Chem 276: 16015–16023, 2001.
111. De Gentile A, Toubert ME, Dubois C, Krawice I, Schlageter MH, Balitrand N,
Castaigne S, Degos L, Rain JD, Najean Y. Induction of high-affinity GM-CSF receptors
during all-trans retinoic acid treatment of acute promyelocytic leukemia. Leukemia 8:
1758 –1762, 1994.
112. De Luca LM. Retinoids and their receptors in differentiation, embryogenesis, and
neoplasia. FASEB J 5: 2924 –2933, 1991.
93. Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis.
Leukemia 16: 1896 –1905, 2002.
113. De The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation
of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a
novel transcribed locus. Nature 347: 558 –561, 1990.
94. Colston KW, Evans IM, Spelsberg TC, MacIntyre I. Feedback regulation of vitamin D
metabolism by 1,25-dihydroxycholecalciferol. Biochem J 164: 83– 89, 1977.
114. De The H, Marchio A, Tiollais P, Dejean A. Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes. EMBO J 8: 429 – 433, 1989.
95. Conesa-Botella A, Mathieu C, Colebunders R, Moreno-Reyes R, van Etten E, Lynen L,
Kestens L. Is vitamin D deficiency involved in the immune reconstitution inflammatory
syndrome? AIDS Res Ther 6: 4, 2009.
115. De The H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, Dejean A. Identification of a
retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 343:
177–180, 1990.
96. Cools N, Ponsaerts P, Van Tendeloo VF, Berneman ZN. Balancing between immunity
and tolerance: an interplay between dendritic cells, regulatory T cells, and effector T
cells. J Leukoc Biol 82: 1365–1374, 2007.
116. De Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall J, Perlmann T.
Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science
290: 2140 –2144, 2000.
776
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
82. Chen Y, Green SR, Ho J, Li A, Almazan F, Quehenberger O. The mouse CCR2 gene
is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor gamma ligands. Biochem Biophys Res Commun
332: 188 –193, 2005.
97. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie
F. A functionally specialized population of mucosal CD103⫹ DCs induces Foxp3⫹
regulatory T cells via a TGF-␤ and retinoic acid dependent mechanism. J Exp Med 204:
1757–1764, 2007.
NAGY ET AL.
117. DeBose-Boyd RA, Ou J, Goldstein JL, Brown MS. Expression of sterol regulatory
element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc Natl Acad Sci USA 98: 1477–1482, 2001.
118. Defacque H, Commes T, Legouffe E, Sevilla C, Rossi JF, Rochette-Egly C, Marti J.
Expression of retinoid X receptor alpha is increased upon monocytic cell differentiation. Biochem Biophys Res Commun 220: 315–322, 1996.
119. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am
J Clin Nutr 80: 1689S–1696S, 2004.
120. Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J, Postic C.
ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in
mouse liver. J Clin Invest 118: 956 –964, 2008.
121. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8: 1086 –1094, 2007.
123. Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K,
Derijard B, Desvergne B, Wahli W, Chambon P, Leibowitz MD, Colombel JF, Auwerx
J. Attenuation of colon inflammation through activators of the retinoid X receptor
(RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J Exp Med 193: 827– 838, 2001.
124. Desvergne B, Michalik L, Wahli W. Transcriptional regulation of metabolism. Physiol
Rev 86: 465–514, 2006.
125. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F,
Kouzarides T, Nervi C, Minucci S, Pelicci PG. Methyltransferase recruitment and
DNA hypermethylation of target promoters by an oncogenic transcription factor.
Science 295: 1079 –1082, 2002.
126. Dong X, Craig T, Xing N, Bachman LA, Paya CV, Weih F, McKean DJ, Kumar R, Griffin
MD. Direct transcriptional regulation of RelB by 1alpha,25-dihydroxyvitamin D3 and
its analogs: physiologic and therapeutic implications for dendritic cell function. J Biol
Chem 278: 49378 – 49385, 2003.
127. Douer D, Koeffler HP. Retinoic acid enhances growth of human early erythroid
progenitor cells in vitro. J Clin Invest 69: 1039 –1041, 1982.
128. Drach J, McQueen T, Engel H, Andreeff M, Robertson KA, Collins SJ, Malavasi F,
Mehta K. Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha. Cancer Res 54: 1746 –1752, 1994.
129. Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem 267: 4315– 4324, 2000.
130. Dunlop TW, Vaisanen S, Frank C, Molnar F, Sinkkonen L, Carlberg C. The human
peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol 349: 248 –260, 2005.
137. Faveeuw C, Fougeray S, Angeli V, Fontaine J, Chinetti G, Gosset P, Delerive P,
Maliszewski C, Capron M, Staels B, Moser M, Trottein F. Peroxisome proliferatoractivated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett 486: 261–266, 2000.
138. Fenton MJ, Buras JA, Donnelly RP. IL-4 reciprocally regulates IL-1 and IL-1 receptor
antagonist expression in human monocytes. J Immunol 149: 1283–1288, 1992.
139. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann
F. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells.
Science 311: 83– 87, 2006.
140. Fontaine C, Rigamonti E, Nohara A, Gervois P, Teissier E, Fruchart JC, Staels B,
Chinetti-Gbaguidi G. Liver X receptor activation potentiates the lipopolysaccharide
response in human macrophages. Circ Res 101: 40 – 49, 2007.
141. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxydelta 12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR
gamma. Cell 83: 803– 812, 1995.
142. Frankenberger M, Hauck RW, Frankenberger B, Haussinger K, Maier KL, Heyder J,
Ziegler-Heitbrock HW. All trans-retinoic acid selectively down-regulates matrix metalloproteinase-9 (MMP-9) and up-regulates tissue inhibitor of metalloproteinase-1
(TIMP-1) in human bronchoalveolar lavage cells. Mol Med 7: 263–270, 2001.
143. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D
metabolite. Nature 228: 764 –766, 1970.
144. Friedman AD. Transcriptional control of granulocyte and monocyte development.
Oncogene 26: 6816 – 6828, 2007.
145. Friedman AD. Transcriptional regulation of granulocyte and monocyte development.
Oncogene 21: 3377–3390, 2002.
146. Fritah A, Christian M, Parker MG. The metabolic coregulator RIP140: an update. Am
J Physiol Endocrinol Metab 299: E335–E340, 2010.
147. Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M. Regulation of 25hydroxyvitamin D3–1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells. Blood 102: 3314 –3316, 2003.
148. Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG.
27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterolloaded cells. J Biol Chem 276: 38378 –38387, 2001.
149. Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol
metabolism by parathyroid glands. Proc Natl Acad Sci USA 69: 1673–1676, 1972.
150. Gauzzi MC, Purificato C, Donato K, Jin Y, Wang L, Daniel KC, Maghazachi AA,
Belardelli F, Adorini L, Gessani S. Suppressive effect of 1alpha,25-dihydroxyvitamin
D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment
of functional activities and chemotaxis. J Immunol 174: 270 –276, 2005.
131. Duprez E, Lillehaug JR, Gaub MP, Lanotte M. Differential changes of retinoid-Xreceptor (RXR alpha) and its RAR alpha and PML-RAR alpha partners induced by
retinoic acid and cAMP distinguish maturation sensitive and resistant t(15;17) promyelocytic leukemia NB4 cells. Oncogene 12: 2443–2450, 1996.
151. Geissmann F, Gordon S, Hume DA, Mowat AM, Randolph GJ. Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 10: 453– 460.
132. Dzhagalov I, Chambon P, He YW. Regulation of CD8⫹ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor
gamma. J Immunol 178: 2113–2121, 2007.
153. Geissmann F, Revy P, Brousse N, Lepelletier Y, Folli C, Durandy A, Chambon P, Dy
M. Retinoids regulate survival and antigen presentation by immature dendritic cells. J
Exp Med 198: 623– 634, 2003.
133. Ehrchen J, Helming L, Varga G, Pasche B, Loser K, Gunzer M, Sunderkotter C, Sorg C,
Roth J, Lengeling A. Vitamin D receptor signaling contributes to susceptibility to
infection with Leishmania major. FASEB J 21: 3208 –3218, 2007.
154. Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan
R, Mangelsdorf DJ, Gronemeyer H. International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58: 760 –772, 2006.
134. Elgueta R, Sepulveda FE, Vilches F, Vargas L, Mora JR, Bono MR, Rosemblatt M.
Imprinting of CCR9 on CD4 T cells requires IL-4 signaling on mesenteric lymph node
dendritic cells. J Immunol 180: 6501– 6507, 2008.
155. Gery S, Park DJ, Vuong PT, Virk RK, Muller CI, Hofmann WK, Koeffler HP. RTP801 is
a novel retinoic acid-responsive gene associated with myeloid differentiation. Exp
Hematol 35: 572–578, 2007.
135. Endo I, Inoue D, Mitsui T, Umaki Y, Akaike M, Yoshizawa T, Kato S, Matsumoto T.
Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle
development with deregulated expression of myoregulatory transcription factors.
Endocrinology 144: 5138 –5144, 2003.
156. Geyeregger R, Zeyda M, Bauer W, Kriehuber E, Saemann MD, Zlabinger GJ, Maurer
D, Stulnig TM. Liver X receptors regulate dendritic cell phenotype and function
through blocked induction of the actin-bundling protein fascin. Blood 109: 4288 –
4295, 2007.
152. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets
with distinct migratory properties. Immunity 19: 71– 82, 2003.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
777
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
122. DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV,
Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S,
Jabri B. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity
to dietary antigens. Nature 471: 220 –224, 2011.
136. Fabriek BO, Van Haastert ES, Galea I, Polfliet MM, Dopp ED, Van Den Heuvel MM,
Van Den Berg TK, De Groot CJ, Van Der Valk P, Dijkstra CD. CD163-positive
perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51: 297–305, 2005.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
157. Ghisletti S, Huang W, Ogawa S, Pascual G, Lin ME, Willson TM, Rosenfeld MG, Glass
CK. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific
transrepression by LXRs and PPARgamma. Mol Cell 25: 57–70, 2007.
158. Gianni M, Terao M, Zanotta S, Barbui T, Rambaldi A, Garattini E. Retinoic acid and
granulocyte colony-stimulating factor synergistically induce leukocyte alkaline phosphatase in acute promyelocytic leukemia cells. Blood 83: 1909 –1921, 1994.
159. Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen
retinoic acid. Nature 330: 624 – 629, 1987.
160. Gilles S, Mariani V, Bryce M, Mueller MJ, Ring J, Jakob T, Pastore S, Behrendt H,
Traidl-Hoffmann C. Pollen-derived E1-phytoprostanes signal via PPAR-gamma and
NF-kappaB-dependent mechanisms. J Immunol 182: 6653– 6658, 2009.
161. Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and
immunity. Nat Rev Immunol 6: 44 –55, 2006.
162. Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 10: 365–376, 2010.
Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in
promyelocytic leukaemia. Nature 391: 815– 818, 1998.
179. Guerriero A, Langmuir PB, Spain LM, Scott EW. PU.1 is required for myeloid-derived
but not lymphoid-derived dendritic cells. Blood 95: 879 – 885, 2000.
180. Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S, Zelent A. Reduced retinoic
acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia.
Blood 91: 2634 –2642, 1998.
181. Guilliams M, Crozat K, Henri S, Tamoutounour S, Grenot P, Devilard E, de Bovis B,
Alexopoulou L, Dalod M, Malissen B. Skin-draining lymph nodes contain dermisderived CD103(⫺) dendritic cells that constitutively produce retinoic acid and induce
Foxp3(⫹) regulatory T cells. Blood 115: 1958 –1968, 2010.
182. Hackstein H, Thomson AW. Dendritic cells: emerging pharmacological targets of
immunosuppressive drugs. Nat Rev Immunol 4: 24 –34, 2004.
164. Goerdt S, Kolde G, Bonsmann G, Hamann K, Czarnetzki B, Andreesen R, Luger T,
Sorg C. Immunohistochemical comparison of cutaneous histiocytoses and related skin
disorders: diagnostic and histogenetic relevance of MS-1 high molecular weight protein expression. J Pathol 170: 421– 427, 1993.
184. Hall JA, Cannons JL, Grainger JR, Dos Santos LM, Hand TW, Naik S, Wohlfert EA,
Chou DB, Oldenhove G, Robinson M, Grigg ME, Kastenmayer R, Schwartzberg PL,
Belkaid Y. Essential role for retinoic acid in the promotion of CD4(⫹) T cell effector
responses via retinoic acid receptor alpha. Immunity 34: 435– 447, 2011.
165. Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigenpresenting cells. Immunity 10: 137–142, 1999.
185. Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC. Role of
alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 152:
3282–3293, 1994.
166. Gogolak P, Rethi B, Szatmari I, Lanyi A, Dezso B, Nagy L, Rajnavolgyi E. Differentiation
of CD1a- and CD1a⫹ monocyte-derived dendritic cells is biased by lipid environment
and PPARgamma. Blood 109: 643– 652, 2007.
167. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide
(CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated
in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 19: 1067–1077, 2005.
168. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 3: 23–35, 2003.
169. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:
953–964, 2005.
170. Gosset P, Charbonnier AS, Delerive P, Fontaine J, Staels B, Pestel J, Tonnel AB,
Trottein F. Peroxisome proliferator-activated receptor gamma activators affect the
maturation of human monocyte-derived dendritic cells. Eur J Immunol 31: 2857–2865,
2001.
186. Hammad H, de Heer HJ, Soullie T, Angeli V, Trottein F, Hoogsteden HC, Lambrecht
BN. Activation of peroxisome proliferator-activated receptor-gamma in dendritic
cells inhibits the development of eosinophilic airway inflammation in a mouse model of
asthma. Am J Pathol 164: 263–271, 2004.
187. Hammerschmidt SI, Ahrendt M, Bode U, Wahl B, Kremmer E, Forster R, Pabst O.
Stromal mesenteric lymph node cells are essential for the generation of gut-homing T
cells in vivo. J Exp Med 205: 2483–2490, 2008.
188. Han KH, Chang MK, Boullier A, Green SR, Li A, Glass CK, Quehenberger O. Oxidized
LDL reduces monocyte CCR2 expression through pathways involving peroxisome
proliferator-activated receptor gamma. J Clin Invest 106: 793– 802, 2000.
189. Han S, Sidell N. Peroxisome-proliferator-activated-receptor gamma (PPARgamma)
independent induction of CD36 in THP-1 monocytes by retinoic acid. Immunology
106: 53–59, 2002.
171. Gottfried E, Rehli M, Hahn J, Holler E, Andreesen R, Kreutz M. Monocyte-derived
cells express CYP27A1 and convert vitamin D3 into its active metabolite. Biochem
Biophys Res Commun 349: 209 –213, 2006.
190. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged
sword. Nat Rev Immunol 6: 508 –519, 2006.
172. Goyette P, Feng Chen C, Wang W, Seguin F, Lohnes D. Characterization of retinoic
acid receptor-deficient keratinocytes. J Biol Chem 275: 16497–16505, 2000.
191. Hartwell D, Hassager C, Christiansen C. Effect of vitamin D2 and vitamin D3 on the
serum concentrations of 1,25(OH)2D2, 1,25(OH)2D3 in normal subjects. Acta Endocrinol 115: 378 –384, 1987.
173. Gratchev A, Guillot P, Hakiy N, Politz O, Orfanos CE, Schledzewski K, Goerdt S.
Alternatively activated macrophages differentially express fibronectin and its splice
variants and the extracellular matrix protein betaIG-H3. Scand J Immunol 53: 386 –
392, 2001.
174. Grefhorst A, Elzinga BM, Voshol PJ, Plosch T, Kok T, Bloks VW, van der Sluijs FH,
Havekes LM, Romijn JA, Verkade HJ, Kuipers F. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277: 34182–34190, 2002.
175. Gresham GA, Howard AN. The histogenesis of the atherosclerotic “fatty streak.” J
Atheroscler Res 1: 413– 416, 1961.
176. Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R. Dendritic cell
modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptordependent pathway that promotes a persistent state of immaturity in vitro and in vivo.
Proc Natl Acad Sci USA 98: 6800 – 6805, 2001.
177. Griffin MD, Lutz WH, Phan VA, Bachman LA, McKean DJ, Kumar R. Potent inhibition
of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys
Res Commun 270: 701–708, 2000.
178. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M,
Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG.
778
192. Haunerland NH, Spener F. Fatty acid-binding proteins–insights from genetic manipulations. Prog Lipid Res 43: 328 –349, 2004.
193. He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP. Distinct
interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine
differential responses to RA in APL. Nat Genet 18: 126 –135, 1998.
194. Helming L, Bose J, Ehrchen J, Schiebe S, Frahm T, Geffers R, Probst-Kepper M, Balling
R, Lengeling A. 1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon
gamma-mediated macrophage activation. Blood 106: 4351– 4358, 2005.
195. Henrich VC, Sliter TJ, Lubahn DB, MacIntyre A, Gilbert LI. A steroid/thyroid hormone
receptor superfamily member in Drosophila melanogaster that shares extensive sequence similarity with a mammalian homologue. Nucleic Acids Res 18: 4143– 4148,
1990.
196. Herbert KE, Walkley CR, Winkler IG, Hendy J, Olsen GH, Yuan YD, Chandraratna
RA, Prince HM, Levesque JP, Purton LE. Granulocyte colony-stimulating factor and an
RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of
hematopoietic progenitor cells. Transplantation 83: 375–384, 2007.
197. Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, Watt
MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass
CK, Ricote M. Macrophage PPAR gamma is required for normal skeletal muscle and
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
163. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell 104: 503–516, 2001.
183. Hakeda Y, Hiura K, Sato T, Okazaki R, Matsumoto T, Ogata E, Ishitani R, Kumegawa
M. Existence of parathyroid hormone binding sites on murine hemopoietic blast cells.
Biochem Biophys Res Commun 163: 1481–1486, 1989.
NAGY ET AL.
hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest
117: 1658 –1669, 2007.
198. Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD,
Moss PA, Chakraverty R. Differential regulation of vitamin D receptor and its ligand in
human monocyte-derived dendritic cells. J Immunol 170: 5382–5390, 2003.
199. Hewison M, Zehnder D, Bland R, Stewart PM. 1alpha-Hydroxylase and the action of
vitamin D. J Mol Endocrinol 25: 141–148, 2000.
200. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C. 9-Cis
retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397– 406,
1992.
201. Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P, Belkaid Y, Mathis D,
Benoist C. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition
from CD4⫹CD44hi Cells. Immunity 29: 758 –770, 2008.
202. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 420:
333–336, 2002.
204. Holick MF. Vitamin D deficiency. N Engl J Med 357: 266 –281, 2007.
205. Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of
1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry 10: 2799 –2804, 1971.
206. Hollis BW, Horst RL. The assessment of circulating 25(OH)D and 1,25(OH)2D:
where we are and where we are going. J Steroid Biochem Mol Biol 103: 473– 476, 2007.
207. Hollis BW, Kamerud JQ, Kurkowski A, Beaulieu J, Napoli JL. Quantification of circulating 1,25-dihydroxyvitamin D by radioimmunoassay with 125I-labeled tracer. Clin
Chem 42: 586 –592, 1996.
208. Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL. Determination of vitamin D
status by radioimmunoassay with an 125I-labeled tracer. Clin Chem 39: 529 –533,
1993.
209. Hollis BW, Pittard WB 3rd. Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J Clin Endocrinol Metab 59: 652– 657,
1984.
210. Homey B, Alenius H, Muller A, Soto H, Bowman EP, Yuan W, McEvoy L, Lauerma AI,
Assmann T, Bunemann E, Lehto M, Wolff H, Yen D, Marxhausen H, To W, Sedgwick
J, Ruzicka T, Lehmann P, Zlotnik A. CCL27-CCR10 interactions regulate T cellmediated skin inflammation. Nat Med 8: 157–165, 2002.
211. Hong C, Tontonoz P. Coordination of inflammation and metabolism by PPAR and
LXR nuclear receptors. Curr Opin Genet Dev 18: 461– 467, 2008.
220. Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol 181: 5829 –
5835, 2008.
221. Im HJ, Craig TA, Pittelkow MR, Kumar R. Characterization of a novel hexameric
repeat DNA sequence in the promoter of the immediate early gene, IEX-1, that
mediates 1alpha,25-dihydroxyvitamin D(3)-associated IEX-1 gene repression. Oncogene 21: 3706 –3714, 2002.
222. Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman
RM. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp
Med 176: 1693–1702, 1992.
223. Ishimoto K, Tachibana K, Sumitomo M, Omote S, Hanano I, Yamasaki D, Watanabe Y,
Tanaka T, Hamakubo T, Sakai J, Kodama T, Doi T. Identification of human low-density
lipoprotein receptor as a novel target gene regulated by liver X receptor alpha. FEBS
Lett 580: 4929 – 4933, 2006.
224. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in
human muscle is associated with changes in diacylglycerol, protein kinase C, and
IkappaB-alpha. Diabetes 51: 2005–2011, 2002.
225. Itoh T, Fairall L, Amin A, Inab Y, Sznato A, Balint LB, Nagy L, Yamamoto K, Schwabe
JWR. Structural basis for the activation of PPAR␥ by oxidized fatty acids. Nature Struct
Mol Biol 15: 924 –931, 2008.
226. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses.
Nat Immunol 5: 987–995, 2004.
227. Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S, Arinobu Y,
Geary K, Zhang P, Dayaram T, Fenyus ML, Elf S, Chan S, Kastner P, Huettner CS,
Murray R, Tenen DG, Akashi K. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106: 1590 –1600,
2005.
228. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid
imprints gut-homing specificity on T cells. Immunity 21: 527–538, 2004.
229. Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL, Berg PL,
Davidsson T, Powrie F, Johansson-Lindbom B, Agace WW. Small intestinal CD103⫹
dendritic cells display unique functional properties that are conserved between mice
and humans. J Exp Med 205: 2139 –2149, 2008.
230. Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ.
Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and
LXRbeta. Proc Natl Acad Sci USA 96: 266 –271, 1999.
212. Hotamisligil GS. Inflammation and metabolic disorders. Nature 444: 860 – 867, 2006.
231. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling
pathway mediated by the nuclear receptor LXR alpha. Nature 383: 728 –731, 1996.
213. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose
tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95: 2409 –2415, 1995.
232. Ji JD, Kim HJ, Rho YH, Choi SJ, Lee YH, Cheon HJ, Sohn J, Song GG. Inhibition of
IL-10-induced STAT3 activation by 15-deoxy-Delta12,14-prostaglandin J2. Rheumatology 44: 983–988, 2005.
214. Houck KA, Borchert KM, Hepler CD, Thomas JS, Bramlett KS, Michael LF, Burris TP.
T0901317 is a dual LXR/FXR agonist. Mol Genet Metab 83: 184 –187, 2004.
233. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte
inflammatory cytokines. Nature 391: 82– 86, 1998.
215. Housley WJ, O’Conor CA, Nichols F, Puddington L, Lingenheld EG, Zhu L, Clark RB.
PPARgamma regulates retinoic acid-mediated DC induction of Tregs. J Leukoc Biol 86:
293–301, 2009.
234. Jiang SJ, Campbell LA, Berry MW, Rosenfeld ME, Kuo CC. Retinoic acid prevents
Chlamydia pneumoniae-induced foam cell development in a mouse model of atherosclerosis. Microbes Infect 10: 1393–1397, 2008.
216. Hsu HC, Yang K, Kharbanda S, Clinton S, Datta R, Stone RM. All-trans retinoic acid
induces monocyte growth factor receptor (c-fms) gene expression in HL-60 leukemia
cells. Leukemia 7: 458 – 462, 1993.
235. Johnson BS, Chandraratna RA, Heyman RA, Allegretto EA, Mueller L, Collins SJ.
Retinoid X receptor (RXR) agonist-induced activation of dominant-negative RXRretinoic acid receptor alpha403 heterodimers is developmentally regulated during
myeloid differentiation. Mol Cell Biol 19: 3372–3382, 1999.
217. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD,
Conrad D, Glass CK. Interleukin-4-dependent production of PPAR-gamma ligands in
macrophages by 12/15-lipoxygenase. Nature 400: 378 –382, 1999.
218. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C,
O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P,
Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of
NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:
599 – 603, 2001.
236. Johnson BS, Mueller L, Si J, Collins SJ. The cytokines IL-3 and GM-CSF regulate the
transcriptional activity of retinoic acid receptors in different in vitro models of myeloid
differentiation. Blood 99: 746 –753, 2002.
237. Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J,
O’Connell RM, Cheng G, Saez E, Miller JF, Tontonoz P. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119:
299 –309, 2004.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
779
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
203. Hofbauer LC, Heufelder AE. Vitamin D receptor knock-out mice: the expectational
and the exceptional. Eur J Endocrinol 138: 372–373, 1998.
219. Hulten LM, Lindmark H, Diczfalusy U, Bjorkhem I, Ottosson M, Liu Y, Bondjers G,
Wiklund O. Oxysterols present in atherosclerotic tissue decrease the expression of
lipoprotein lipase messenger RNA in human monocyte-derived macrophages. J Clin
Invest 97: 461– 468, 1996.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
238. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation
of inflammation and lipid metabolism by liver X receptors. Nat Med 9: 213–219, 2003.
239. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL,
Osborne TF, Tontonoz P. Direct and indirect mechanisms for regulation of fatty acid
synthase gene expression by liver X receptors. J Biol Chem 277: 11019 –11025, 2002.
240. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G,
Goodman J, Hagger GN, Tran J, Tippin TK, Wang X, Lusis AJ, Hsueh WA, Law RE,
Collins JL, Willson TM, Tontonoz P. Synthetic LXR ligand inhibits the development of
atherosclerosis in mice. Proc Natl Acad Sci USA 99: 7604 –7609, 2002.
241. Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV,
Dmitrovsky E, Evans RM. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.
Cell 66: 663– 674, 1991.
242. Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Kitazume MT, Takayama
T, Okamoto S, Koganei K, Sugita A, Kanai T, Hibi T. Human CD14⫹ macrophages in
intestinal lamina propria exhibit potent antigen-presenting ability. J Immunol 2009.
244. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H,
Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into
adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:
1494 –1505, 2006.
245. Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH. Vitamin A metabolites
induce gut-homing FoxP3⫹ regulatory T cells. J Immunol 179: 3724 –3733, 2007.
246. Kaplan DH. In vivo function of Langerhans cells and dermal dendritic cells. Trends
Immunol 31: 446 – 451, 2010.
247. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev
Immunol 3: 984 –993, 2003.
248. Kastner P, Chan S. Function of RARalpha during the maturation of neutrophils. Oncogene 20: 7178 –7185, 2001.
249. Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D, Vonesch JL,
Dolle P, Chambon P. Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78:
987–1003, 1994.
250. Kastner P, Lawrence HJ, Waltzinger C, Ghyselinck NB, Chambon P, Chan S. Positive
and negative regulation of granulopoiesis by endogenous RARalpha. Blood 97: 1314 –
1320, 2001.
251. Kastner P, Mark M, Ghyselinck N, Krezel W, Dupe V, Grondona JM, Chambon P.
Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR
functional units during mouse development. Development 124: 313–326, 1997.
252. Katz DR, Drzymala M, Turton JA, Hicks RM, Hunt R, Palmer L, Malkovsky M. Regulation of accessory cell function by retinoids in murine immune responses. Br J Exp
Pathol 68: 343–350, 1987.
253. Kaufmann SH. Immunology’s foundation: the 100-year anniversary of the Nobel Prize
to Paul Ehrlich and Elie Metchnikoff. Nat Immunol 9: 705–712, 2008.
254. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato
H, Kondo E, Koseki H, Taniguchi M. CD1d-restricted and TCR-mediated activation of
valpha14 NKT cells by glycosylceramides. Science 278: 1626 –1629, 1997.
255. Kennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, Edwards
PA. Characterization of the human ABCG1 gene: liver X receptor activates an internal
promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem 276: 39438 –39447, 2001.
256. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 405:
421– 424, 2000.
257. Kersten S, Kelleher D, Chambon P, Gronemeyer H, Noy N. Retinoid X receptor
alpha forms tetramers in solution. Proc Natl Acad Sci USA 92: 8645– 8649, 1995.
780
259. Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, Romani N, Tripp CH,
Douillard P, Leserman L, Kaiserlian D, Saeland S, Davoust J, Malissen B. Dynamics and
function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas
distinct from slower migrating Langerhans cells. Immunity 22: 643– 654, 2005.
260. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83: 813– 819, 1995.
261. Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts
with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.
Nature 355: 446 – 449, 1992.
262. Klotz L, Dani I, Edenhofer F, Nolden L, Evert B, Paul B, Kolanus W, Klockgether T,
Knolle P, Diehl L. Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4⫹ T cell anergy. J Immunol 178:
2122–2131, 2007.
263. Klotz L, Hucke S, Thimm D, Classen S, Gaarz A, Schultze J, Edenhofer F, Kurts C,
Klockgether T, Limmer A, Knolle P, Burgdorf S. Increased antigen cross-presentation
but impaired cross-priming after activation of peroxisome proliferator-activated receptor gamma is mediated by up-regulation of B7H1. J Immunol 183: 129 –136, 2009.
264. Kodelja V, Muller C, Politz O, Hakij N, Orfanos CE, Goerdt S. Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern. J
Immunol 160: 1411–1418, 1998.
265. Kodelja V, Muller C, Tenorio S, Schebesch C, Orfanos CE, Goerdt S. Differences in
angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197: 478 – 493, 1997.
266. Koeffler HP, Amatruda T, Ikekawa N, Kobayashi Y, DeLuca HF. Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25dihydroxyvitamin D3 and its fluorinated analogues. Cancer Res 44: 5624 –5628, 1984.
267. Koren R, Ravid A, Rotem C, Shohami E, Liberman UA, Novogrodsky A. 1,25-Dihydroxyvitamin D3 enhances prostaglandin E2 production by monocytes. A mechanism
which partially accounts for the antiproliferative effect of 1,25(OH)2D3 on lymphocytes. FEBS Lett 205: 113–116, 1986.
268. Kostrouch Z, Kostrouchova M, Love W, Jannini E, Piatigorsky J, Rall JE. Retinoic acid
X receptor in the diploblast, Tripedalia cystophora. Proc Natl Acad Sci USA 95: 13442–
13447, 1998.
269. Kreutz M, Andreesen R, Krause SW, Szabo A, Ritz E, Reichel H. 1,25-Dihydroxyvitamin D3 production and vitamin D3 receptor expression are developmentally regulated during differentiation of human monocytes into macrophages. Blood 82: 1300 –
1307, 1993.
270. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S,
Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara
H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T,
Ezaki O, Aizawa S, Kadowaki T. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4: 597– 609, 1999.
271. Kurokawa R, DiRenzo J, Boehm M, Sugarman J, Gloss B, Rosenfeld MG, Heyman RA,
Glass CK. Regulation of retinoid signalling by receptor polarity and allosteric control of
ligand binding. Nature 371: 528 –531, 1994.
272. Labbaye C, Valtieri M, Testa U, Giampaolo A, Meccia E, Sterpetti P, Parolini I, Pelosi
E, Bulgarini D, Cayre YE. Retinoic acid downmodulates erythroid differentiation and
GATA1 expression in purified adult-progenitor culture. Blood 83: 651– 656, 1994.
273. Labrecque J, Allan D, Chambon P, Iscove NN, Lohnes D, Hoang T. Impaired granulocytic differentiation in vitro in hematopoietic cells lacking retinoic acid receptors
alpha1 and gamma. Blood 92: 607– 615, 1998.
274. Laffitte BA, Joseph SB, Chen M, Castrillo A, Repa J, Wilpitz D, Mangelsdorf D, Tontonoz P. The phospholipid transfer protein gene is a liver X receptor target expressed
by macrophages in atherosclerotic lesions. Mol Cell Biol 23: 2182–2191, 2003.
275. Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, Collins JL, Tontonoz P. Autoregulation of the human liver X receptor alpha promoter. Mol Cell Biol 21: 7558 –
7568, 2001.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
243. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N,
Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S,
Manabe I, Hashimoto H, Ohnishi Y, Ogata H, Tokuyama K, Tsunoda M, Ide T,
Murakami K, Nagai R, Kadowaki T. Overexpression of monocyte chemoattractant
protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J
Biol Chem 281: 26602–26614, 2006.
258. Kim SR, Lee KS, Park HS, Park SJ, Min KH, Jin SM, Lee YC. Involvement of IL-10 in
peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma. Mol Pharmacol 68: 1568 –1575, 2005.
NAGY ET AL.
276. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P.
LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages
and adipocytes. Proc Natl Acad Sci USA 98: 507–512, 2001.
294. Li J, King I, Sartorelli AC. Differentiation of WEHI-3B D⫹ myelomonocytic leukemia
cells induced by ectopic expression of the protooncogene c-jun. Cell Growth Differ 5:
743–751, 1994.
277. Lagishetty V, Misharin AV, Liu NQ, Lisse TS, Chun RF, Ouyang Y, McLachlan SM,
Adams JS, Hewison M. Vitamin D deficiency in mice impairs colonic antibacterial
activity and predisposes to colitis. Endocrinology 151: 2423–2432, 2010.
295. Li Y, Bolten C, Bhat BG, Woodring-Dietz J, Li S, Prayaga SK, Xia C, Lala DS. Induction
of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. Mol Endocrinol 16: 506 –514, 2002.
278. Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R, Gantner BN,
Dinner AR, Singh H. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126: 755–766, 2006.
296. Li Y, Zhang J, Schopfer FJ, Martynowski D, Garcia-Barrio MT, Kovach A, Suino-Powell
K, Baker PR, Freeman BA, Chen YE, Xu HE. Molecular recognition of nitrated fatty
acids by PPAR gamma. Nat Struct Mol Biol 15: 865– 867, 2008.
279. Le Naour F, Hohenkirk L, Grolleau A, Misek DE, Lescure P, Geiger JD, Hanash S,
Beretta L. Profiling changes in gene expression during differentiation and maturation
of monocyte-derived dendritic cells using both oligonucleotide microarrays and proteomics. J Biol Chem 276: 17920 –17931, 2001.
297. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, Demay MB. Targeted
ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets
type II with alopecia. Proc Natl Acad Sci USA 94: 9831–9835, 1997.
280. Lee KS, Park SJ, Hwang PH, Yi HK, Song CH, Chai OH, Kim JS, Lee MK, Lee YC.
PPAR-gamma modulates allergic inflammation through up-regulation of PTEN. FASEB
J 19: 1033–1035, 2005.
282. Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, Feng D, Zhuo D,
Stoeckert CJ Jr, Liu XS, Lazar MA. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev 22: 2941–
2952, 2008.
283. Lehmann JM, Jong L, Fanjul A, Cameron JF, Lu XP, Haefner P, Dawson MI, Pfahl M.
Retinoids selective for retinoid X receptor response pathways. Science 258: 1944 –
1946, 1992.
284. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS,
Winegar DA, Blanchard DE, Spencer TA, Willson TM. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:
3137–3140, 1997.
285. Lehmann S, Paul C, Torma H. Retinoid receptor expression and its correlation to
retinoid sensitivity in non-M3 acute myeloid leukemia blast cells. Clin Cancer Res 7:
367–373, 2001.
286. Lehrke I, Schaier M, Schade K, Morath C, Waldherr R, Ritz E, Wagner J. Retinoid
receptor-specific agonists alleviate experimental glomerulonephritis. Am J Physiol Renal Physiol 282: F741–F751, 2002.
287. Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub
A, Garnier JM, Mader S. Purification, cloning, and RXR identity of the HeLa cell factor
with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 68:
377–395, 1992.
288. Lemire JM, Adams JS, Kermani-Arab V, Bakke AC, Sakai R, Jordan SC. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J
Immunol 134: 3032–3035, 1985.
289. Lemire JM, Adams JS, Sakai R, Jordan SC. 1 Alpha,25-dihydroxyvitamin D3 suppresses
proliferation and immunoglobulin production by normal human peripheral blood
mononuclear cells. J Clin Invest 74: 657– 661, 1984.
290. Lemotte PK, Keidel S, Apfel CM. Phytanic acid is a retinoid X receptor ligand. Eur J
Biochem 236: 328 –333, 1996.
291. Leslie DS, Dascher CC, Cembrola K, Townes MA, Hava DL, Hugendubler LC, Mueller E, Fox L, Roura-Mir C, Moody DB, Vincent MS, Gumperz JE, Illarionov PA, Besra
GS, Reynolds CG, Brenner MB. Serum lipids regulate dendritic cell CD1 expression
and function. Immunology 125: 289 –301, 2008.
292. Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G,
Speck J, Kratzeisen C, Rosenberger M, Lovey A. 9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 355: 359 –361,
1992.
293. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in
LDL receptor-deficient mice. J Clin Invest 106: 523–531, 2000.
299. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391: 811– 814, 1998.
300. Linehan SA, Martinez-Pomares L, Stahl PD, Gordon S. Mannose receptor and its
putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular
microglia, mesangial cells, but not dendritic cells. J Exp Med 189: 1961–1972, 1999.
301. Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, Chu FF,
Randolph GJ, Rudensky AY, Nussenzweig M. In vivo analysis of dendritic cell development and homeostasis. Science 324: 392–397, 2009.
302. Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR partnership. Trends Mol Med 13: 117–124, 2007.
303. Liu PT, Schenk M, Walker VP, Dempsey PW, Kanchanapoomi M, Wheelwright M,
Vazirnia A, Zhang X, Steinmeyer A, Zugel U, Hollis BW, Cheng G, Modlin RL. Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS One 4: e5810, 2009.
304. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K,
Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor
triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770 –
1773, 2006.
305. Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: vitamin D-mediated human
antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction
of cathelicidin. J Immunol 179: 2060 –2063, 2007.
306. Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P. Function of retinoic
acid receptor gamma in the mouse. Cell 73: 643– 658, 1993.
307. Lohnes D, Mark M, Mendelsohn C, Dolle P, Dierich A, Gorry P, Gansmuller A,
Chambon P. Function of the retinoic acid receptors (RARs) during development (I).
Craniofacial and skeletal abnormalities in RAR double mutants. Development 120:
2723–2748, 1994.
308. Lord KA, Abdollahi A, Hoffman-Liebermann B, Liebermann DA. Proto-oncogenes of
the fos/jun family of transcription factors are positive regulators of myeloid differentiation. Mol Cell Biol 13: 841– 851, 1993.
309. Luo Y, Tall AR. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest 105: 513–520, 2000.
310. Luria A, Furlow JD. Spatiotemporal retinoid-X receptor activation detected in live
vertebrate embryos. Proc Natl Acad Sci USA 101: 8987– 8992, 2004.
311. Lusis AJ. Atherosclerosis. Nature 407: 233–241, 2000.
312. Ma J, Chen T, Mandelin J, Ceponis A, Miller NE, Hukkanen M, Ma GF, Konttinen YT.
Regulation of macrophage activation. Cell Mol Life Sci 60: 2334 –2346, 2003.
313. Mak PA, Kast-Woelbern HR, Anisfeld AM, Edwards PA. Identification of PLTP as an
LXR target gene and apoE as an FXR target gene reveals overlapping targets for the
two nuclear receptors. J Lipid Res 43: 2037–2041, 2002.
314. Mak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK, Mangelsdorf DJ, Tontonoz
P, Edwards PA. Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene
cluster in murine and human macrophages. A critical role for nuclear liver X receptors
alpha and beta. J Biol Chem 277: 31900 –31908, 2002.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
781
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
281. Lee SJ, Yang EK, Kim SG. Peroxisome proliferator-activated receptor-gamma and
retinoic acid X receptor alpha represses the TGFbeta1 gene via PTEN-mediated p70
ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation. Mol Pharmacol 70:
415– 425, 2006.
298. Libby P. Inflammation in atherosclerosis. Nature 420: 868 – 874, 2002.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
315. Malerod L, Juvet LK, Hanssen-Bauer A, Eskild W, Berg T. Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes.
Biochem Biophys Res Commun 299: 916 –923, 2002.
335. Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their
roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215,
1999.
316. Maly P, Thall A, Petryniak B, Rogers CE, Smith PL, Marks RM, Kelly RJ, Gersten KM,
Cheng G, Saunders TL, Camper SA, Camphausen RT, Sullivan FX, Isogai Y, Hindsgaul
O, von Andrian UH, Lowe JB. The alpha(1,3)fucosyltransferase Fuc-TVII controls
leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell 86: 643– 653, 1996.
336. Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, Mark M.
Function of the retinoic acid receptors (RARs) during development (II). Multiple
abnormalities at various stages of organogenesis in RAR double mutants. Development
120: 2749 –2771, 1994.
317. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A,
Evans RM. Characterization of three RXR genes that mediate the action of 9-cis
retinoic acid. Genes Dev 6: 329 –344, 1992.
318. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell 83:
841– 850, 1995.
319. Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor that identifies a novel
retinoic acid response pathway. Nature 345: 224 –229, 1990.
321. Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang YC,
Pulendran B. Activation of beta-catenin in dendritic cells regulates immunity versus
tolerance in the intestine. Science 329: 849 – 853, 2010.
322. Marathe C, Bradley MN, Hong C, Chao L, Wilpitz D, Salazar J, Tontonoz P. Preserved
glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma⫺/⫺,
PPARdelta⫺/⫺, PPARgammadelta⫺/⫺, or LXRalphabeta⫺/⫺ bone marrow. J Lipid
Res 50: 214 –224, 2009.
323. Mark M, Ghyselinck NB, Chambon P. Function of retinoic acid receptors during
embryonic development. Nucl Recept Signal 7: e002, 2009.
324. Martinez-Pomares L, Gordon S. Antigen presentation the macrophage way. Cell 131:
641– 643, 2007.
325. Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARgamma activation in human
endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol 19:
546 –551, 1999.
326. Mathieu C, Adorini L. The coming of age of 1,25-dihydroxyvitamin D(3) analogs as
immunomodulatory agents. Trends Mol Med 8: 174 –179, 2002.
338. Meunier L, Bohjanen K, Voorhees JJ, Cooper KD. Retinoic acid upregulates human
Langerhans cell antigen presentation and surface expression of HLA-DR and CD11c,
a beta 2 integrin critically involved in T-cell activation. J Invest Dermatol 103: 775–779,
1994.
339. Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, Saez E. The
nuclear receptor LXR is a glucose sensor. Nature 445: 219 –223, 2007.
340. Mitro N, Vargas L, Romeo R, Koder A, Saez E. T0901317 is a potent PXR ligand:
implications for the biology ascribed to LXR. FEBS Lett 581: 1721–1726, 2007.
341. Moghadasian MH, Salen G, Frohlich JJ, Scudamore CH. Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations. Arch Neurol 59: 527–529, 2002.
342. Mohty M, Morbelli S, Isnardon D, Sainty D, Arnoulet C, Gaugler B, Olive D. All-trans
retinoic acid skews monocyte differentiation into interleukin-12-secreting dendriticlike cells. Br J Haematol 122: 829 – 836, 2003.
343. Molenaar R, Greuter M, van der Marel AP, Roozendaal R, Martin SF, Edele F, Huehn
J, Forster R, O’Toole T, Jansen W, Eestermans IL, Kraal G, Mebius RE. Lymph node
stromal cells support dendritic cell-induced gut-homing of T cells. J Immunol 183:
6395– 6402, 2009.
344. Molenaar R, Knippenberg M, Goverse G, Olivier BJ, de Vos AF, O’Toole T, Mebius
RE. Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells
and gut-draining lymph node stromal cells is controlled by dietary vitamin A. J Immunol
186: 1934 –1942, 2011.
345. Molteni V, Li X, Nabakka J, Liang F, Wityak J, Koder A, Vargas L, Romeo R, Mitro N,
Mak PA, Seidel HM, Haslam JA, Chow D, Tuntland T, Spalding TA, Brock A, Bradley
M, Castrillo A, Tontonoz P, Saez E. N-Acylthiadiazolines, a new class of liver X
receptor agonists with selectivity for LXRbeta. J Med Chem 50: 4255– 4259, 2007.
327. Matikainen S, Ronni T, Hurme M, Pine R, Julkunen I. Retinoic acid activates interferon
regulatory factor-1 gene expression in myeloid cells. Blood 88: 114 –123, 1996.
346. Montemurro P, Barbuti G, Conese M, Gabriele S, Petio M, Colucci M, Semeraro N.
Retinoic acid stimulates plasminogen activator inhibitor 2 production by blood mononuclear cells and inhibits urokinase-induced extracellular proteolysis. Br J Haematol
107: 294 –299, 1999.
328. Maynard CL, Hatton RD, Helms WS, Oliver JR, Stephensen CB, Weaver CT. Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of Foxp3 and
Il10 genes in developing regulatory T cells. J Exp Med 206: 343–357, 2009.
347. Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone
DS, Mortensen RM, Spiegelman BM, Freeman MW. The role of PPAR-gamma in
macrophage differentiation and cholesterol uptake. Nat Med 7: 41– 47, 2001.
329. McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D,
Wilson PW, Jacques P. Relation of dietary intake and serum levels of vitamin D to
progression of osteoarthritis of the knee among participants in the Framingham Study.
Ann Intern Med 125: 353–359, 1996.
348. Mora JR. Homing imprinting and immunomodulation in the gut: role of dendritic cells
and retinoids. Inflamm Bowel Dis 14: 275–289, 2008.
330. McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemsz
M, Feeney AJ, Wu GE, Paige CJ, Maki RA. Targeted disruption of the PU.1 gene results
in multiple hematopoietic abnormalities. EMBO J 15: 5647–5658, 1996.
331. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394 –397,
1997.
332. Meehan MA, Kerman RH, Lemire JM. 1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells
in a human MLR. Cell Immunol 140: 400 – 409, 1992.
333. Mehta K, McQueen T, Neamati N, Collins S, Andreeff M. Activation of retinoid
receptors RAR alpha and RXR alpha induces differentiation and apoptosis, respectively, in HL-60 cells. Cell Growth Differ 7: 179 –186, 1996.
334. Mehta K, McQueen T, Tucker S, Pandita R, Aggarwal BB. Inhibition by all-transretinoic acid of tumor necrosis factor and nitric oxide production by peritoneal macrophages. J Leukoc Biol 55: 336 –342, 1994.
782
349. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A,
Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, Adams DH, von Andrian UH. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314:
1157–1160, 2006.
350. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins
A and D take centre stage. Nat Rev Immunol 2008.
351. Morales J, Homey B, Vicari AP, Hudak S, Oldham E, Hedrick J, Orozco R, Copeland
NG, Jenkins NA, McEvoy LM, Zlotnik A. CTACK, a skin-associated chemokine that
preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci USA 96: 14470 –
14475, 1999.
352. Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant
tolerance. Nat Rev Immunol 7: 610 – 621, 2007.
353. Mosser DM. The many faces of macrophage activation. J Leukoc Biol 73: 209 –212,
2003.
354. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat
Rev Immunol 8: 958 –969, 2008.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
320. Manicassamy S, Ravindran R, Deng J, Oluoch H, Denning TL, Kasturi SP, Rosenthal
KM, Evavold BD, Pulendran B. Toll-like receptor 2-dependent induction of vitamin
A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med 15: 401– 409, 2009.
337. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is
inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health
Study. Arthritis Rheum 50: 72–77, 2004.
NAGY ET AL.
355. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H.
Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256 –260, 2007.
356. Mucida D, Pino-Lagos K, Kim G, Nowak E, Benson MJ, Kronenberg M, Noelle RJ,
Cheroutre H. Retinoic acid can directly promote TGF-beta-mediated Foxp3(⫹) Treg
cell conversion of naive T cells. Immunity 30: 471– 473, 2009.
357. Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U, Tenen DG. ATRA
resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring
PU.1 expression. Blood 107: 3330 –3338, 2006.
358. Mues B, Langer D, Zwadlo G, Sorg C. Phenotypic characterization of macrophages in
human term placenta. Immunology 67: 303–307, 1989.
359. Mukherjee R, Davies PJ, Crombie DL, Bischoff ED, Cesario RM, Jow L, Hamann LG,
Boehm MF, Mondon CE, Nadzan AM, Paterniti JR Jr, Heyman RA. Sensitization of
diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 386:
407– 410, 1997.
361. Munder M, Eichmann K, Moran JM, Centeno F, Soler G, Modolell M. Th1/Th2regulated expression of arginase isoforms in murine macrophages and dendritic cells.
J Immunol 163: 3771–3777, 1999.
362. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, Ascherio A.
Vitamin D intake and incidence of multiple sclerosis. Neurology 62: 60 – 65, 2004.
374. Nakajima H, Kizaki M, Ueno H, Muto A, Takayama N, Matsushita H, Sonoda A, Ikeda
Y. All-trans and 9-cis retinoic acid enhance 1,25-dihydroxyvitamin D3-induced monocytic differentiation of U937 cells. Leukoc Res 20: 665– 676, 1996.
375. Nakken B, Varga T, Szatmari I, Szeles L, Gyongyosi A, Illarionov PA, Dezso B, Gogolak
P, Rajnavolgyi E, Nagy L. Peroxisome proliferator-activated receptor gamma-regulated cathepsin D is required for lipid antigen presentation by dendritic cells. J Immunol
187: 240 –247, 2011.
376. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson
MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. AMPK and PPARdelta agonists
are exercise mimetics. Cell 134: 405– 415, 2008.
377. Navab M, Berliner JA, Watson AD, Hama SY, Territo MC, Lusis AJ, Shih DM, Van
Lenten BJ, Frank JS, Demer LL, Edwards PA, Fogelman AM. The Yin and Yang of
oxidation in the development of the fatty streak. A review based on the 1994 George
Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol 16: 831– 842, 1996.
378. Nencioni A, Grunebach F, Zobywlaski A, Denzlinger C, Brugger W, Brossart P.
Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor gamma. J Immunol 169: 1228 –1235, 2002.
379. Niederreither K, Subbarayan V, Dolle P, Chambon P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21:
444 – 448, 1999.
363. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of
T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189: 1363–1372,
1999.
380. Nielsen R, Pedersen TA, Hagenbeek D, Moulos P, Siersbaek R, Megens E, Denissov S,
Borgesen M, Francoijs KJ, Mandrup S, Stunnenberg HG. Genome-wide profiling of
PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of
distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev 22: 2953–2967, 2008.
364. Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T, Kato S. The promoter of
the human 25-hydroxyvitamin D3 1 alpha-hydroxylase gene confers positive and
negative responsiveness to PTH, calcitonin, and 1 alpha,25(OH)2D3. Biochem Biophys
Res Commun 249: 11–16, 1998.
381. Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic
review and meta-analysis. Int J Epidemiol 37: 113–119, 2008.
365. Na G, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C,
Diaz M, Gallardo G, de Galarreta CR, Salazar J, Lopez F, Edwards P, Parks J, Andujar
M, Tontonoz P, Castrillo A. Apoptotic cells promote their own clearance and immune
tolerance through activation of the nuclear receptor LXR. Immunity 31: 245–258,
2009.
366. Na SY, Kang BY, Chung SW, Han SJ, Ma X, Trinchieri G, Im SY, Lee JW, Kim TS.
Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB. J Biol Chem 274: 7674 –7680,
1999.
367. Nagy L, Saydak M, Shipley N, Lu S, Basilion JP, Yan ZH, Syka P, Chandraratna RA, Stein
JP, Heyman RA, Davies PJ. Identification and characterization of a versatile retinoid
response element (retinoic acid receptor response element-retinoid X receptor response element) in the mouse tissue transglutaminase gene promoter. J Biol Chem
271: 4355– 4365, 1996.
368. Nagy L, Schwabe JW. Mechanism of the nuclear receptor molecular switch. Trends
Biochem Sci 29: 317–324, 2004.
369. Nagy L, Thomazy VA, Chandraratna RA, Heyman RA, Davies PJ. Retinoid-regulated
expression of BCL-2 and tissue transglutaminase during the differentiation and apoptosis of human myeloid leukemia (HL-60) cells. Leuk Res 20: 499 –505, 1996.
370. Nagy L, Thomazy VA, Shipley GL, Fesus L, Lamph W, Heyman RA, Chandraratna RA,
Davies PJ. Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol
Cell Biol 15: 3540 –3551, 1995.
371. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93: 229 –240,
1998.
372. Naik SH, Sathe P, Park HY, Metcalf D, Proietto AI, Dakic A, Carotta S, O’Keeffe M,
Bahlo M, Papenfuss A, Kwak JY, Wu L, Shortman K. Development of plasmacytoid and
conventional dendritic cell subtypes from single precursor cells derived in vitro and in
vivo. Nat Immunol 8: 1217–1226, 2007.
373. Nakajima H, Kizaki M, Sonoda A, Mori S, Harigaya K, Ikeda Y. Retinoids (all-trans and
9-cis retinoic acid) stimulate production of macrophage colony-stimulating factor and
382. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG,
Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the
peroxisome proliferator-activated receptor-gamma. Nature 395: 137–143, 1998.
383. Norbury CC. Drinking a lot is good for dendritic cells. Immunology 117: 443– 451,
2006.
384. Nozaki Y, Yamagata T, Sugiyama M, Ikoma S, Kinoshita K, Funauchi M. Anti-inflammatory effect of all-trans-retinoic acid in inflammatory arthritis. Clin Immunol 119:
272–279, 2006.
385. Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary
treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta
Med Indones 38: 3–5, 2006.
386. Odegaard JI, Chawla A. Mechanisms of macrophage activation in obesity-induced
insulin resistance. Nat Clin Pract Endocrinol Metab 4: 619 – 626, 2008.
387. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Eagle AR, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific
PPARgamma controls alternative activation and improves insulin resistance. Nature
447: 1116 –1120, 2007.
388. Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A,
Subramaniam S, David M, Rosenfeld MG, Glass CK. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122: 707–721, 2005.
389. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T,
Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB,
Nunez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to
Crohn’s disease. Nature 411: 603– 606, 2001.
390. Ohoka Y, Yokota A, Takeuchi H, Maeda N, Iwata M. Retinoic acid-induced CCR9
expression requires transient TCR stimulation and cooperativity between NFATc2
and the retinoic acid receptor/retinoid X receptor complex. J Immunol 186: 733–744,
2011.
391. Ohta M, Okabe T, Ozawa K, Urabe A, Takaku F. 1 alpha,25-Dihydroxyvitamin D3
(calcitriol) stimulates proliferation of human circulating monocytes in vitro. FEBS Lett
185: 9 –13, 1985.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
783
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
360. Muller K, Heilmann C, Poulsen LK, Barington T, Bendtzen K. The role of monocytes
and T cells in 1,25-dihydroxyvitamin D3 mediated inhibition of B cell function in vitro.
Immunopharmacology 21: 121–128, 1991.
granulocyte-macrophage colony-stimulating factor by human bone marrow stromal
cells. Blood 84: 4107– 4115, 1994.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
392. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev
Physiol 72: 219 –246.
393. Onai N, Obata-Onai A, Schmid MA, Ohteki T, Jarrossay D, Manz MG. Identification of
clonogenic common Flt3⫹M-CSFR⫹ plasmacytoid and conventional dendritic cell
progenitors in mouse bone marrow. Nat Immunol 8: 1207–1216, 2007.
394. Orban TI, Apati A, Nemeth A, Varga N, Krizsik V, Schamberger A, Szebenyi K, Erdei
Z, Varady G, Karaszi E, Homolya L, Nemet K, Gocza E, Miskey C, Mates L, Ivics Z,
Izsvak Z, Sarkadi B. Applying a “double-feature” promoter to identify cardiomyocytes
differentiated from human embryonic stem cells following transposon-based gene
delivery. Stem Cells 27: 1077–1087, 2009.
412. Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo
V. Vitamin D3 affects differentiation, maturation, and function of human monocytederived dendritic cells. J Immunol 164: 4443– 4451, 2000.
413. Pierce A, Heyworth CM, Nicholls SE, Spooncer E, Dexter TM, Lord JM, Owen-Lynch
PJ, Wark G, Whetton AD. An activated protein kinase C alpha gives a differentiation
signal for hematopoietic progenitor cells and mimicks macrophage colony-stimulating
factor-stimulated signaling events. J Cell Biol 140: 1511–1518, 1998.
414. Pikuleva IA, Babiker A, Waterman MR, Bjorkhem I. Activities of recombinant human
cytochrome P450c27 (CYP27) which produce intermediates of alternative bile acid
biosynthetic pathways. J Biol Chem 273: 18153–18160, 1998.
415. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva
M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective
LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science
282: 2085–2088, 1998.
396. Oro AE, McKeown M, Evans RM. Relationship between the product of the Drosophila
ultraspiracle locus and the vertebrate retinoid X receptor. Nature 347: 298 –301,
1990.
416. Portale AA, Halloran BP, Murphy MM, Morris RC Jr. Oral intake of phosphorus can
determine the serum concentration of 1,25-dihydroxyvitamin D by determining its
production rate in humans. J Clin Invest 77: 7–12, 1986.
397. Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA. Dendritic cell development and survival
require distinct NF-kappaB subunits. Immunity 16: 257–270, 2002.
417. Powell WS. 15-Deoxy-delta12,14-PGJ2: endogenous PPARgamma ligand or minor
eicosanoid degradation product? J Clin Invest 112: 828 – 830, 2003.
398. Pai T, Chen Q, Zhang Y, Zolfaghari R, Ross AC. Galactomutarotase and other galactose-related genes are rapidly induced by retinoic acid in human myeloid cells. Biochemistry 46: 15198 –15207, 2007.
418. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D.
Trends Biochem Sci 29: 664 – 673, 2004.
399. Park DJ, Chumakov AM, Vuong PT, Chih DY, Gombart AF, Miller WH Jr, Koeffler HP.
CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute
promyelocytic leukemia treatment. J Clin Invest 103: 1399 –1408, 1999.
400. Park EJ, Park SY, Joe EH, Jou I. 15d-PGJ2 and rosiglitazone suppress Janus kinaseSTAT inflammatory signaling through induction of suppressor of cytokine signaling 1
(SOCS1) and SOCS3 in glia. J Biol Chem 278: 14747–14752, 2003.
401. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM,
Rosenfeld MG, Glass CK. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437: 759 –763, 2005.
402. Pascual G, Glass CK. Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol Metab 17: 321–327, 2006.
403. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH. Tumor suppressor and
anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of
PTEN. Curr Biol 11: 764 –768, 2001.
404. Peet DJ, Janowski BA, Mangelsdorf DJ. The LXRs: a new class of oxysterol receptors.
Curr Opin Genet Dev 8: 571–575, 1998.
405. Penna G, Adorini L. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell
activation. J Immunol 164: 2405–2411, 2000.
406. Penna G, Amuchastegui S, Giarratana N, Daniel KC, Vulcano M, Sozzani S, Adorini L.
1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid
but not plasmacytoid dendritic cells. J Immunol 178: 145–153, 2007.
407. Penna G, Giarratana N, Amuchastegui S, Mariani R, Daniel KC, Adorini L. Manipulating dendritic cells to induce regulatory T cells. Microbes Infect 7: 1033–1039, 2005.
408. Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L.
Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4⫹Foxp3⫹ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106:
3490 –3497, 2005.
409. Perez de Lema G, Lucio-Cazana FJ, Molina A, Luckow B, Schmid H, de Wit C,
Moreno-Manzano V, Banas B, Mampaso F, Schlondorff D. Retinoic acid treatment
protects MRL/lpr lupus mice from the development of glomerular disease. Kidney Int
66: 1018 –1028, 2004.
419. Pryke AM, Duggan C, White CP, Posen S, Mason RS. Tumor necrosis factor-alpha
induces vitamin D-1-hydroxylase activity in normal human alveolar macrophages. J
Cell Physiol 142: 652– 656, 1990.
420. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density
lipoproteins: a potential role in recruitment and retention of monocyte/macrophages
during atherogenesis. Proc Natl Acad Sci USA 84: 2995–2998, 1987.
421. Raes G, De Baetselier P, Noel W, Beschin A, Brombacher F, Hassanzadeh Gh G.
Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated
macrophages. J Leukoc Biol 71: 597– 602, 2002.
422. Ralph AP, Kelly PM, Anstey NM. L-Arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis. Trends Microbiol 16: 336 –344, 2008.
423. Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA. Differentiation of
phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11: 753–761,
1999.
424. Ravichandran KS, Lorenz U. Engulfment of apoptotic cells: signals for a good meal. Nat
Rev Immunol 7: 964 –974, 2007.
425. Rebe C, Raveneau M, Chevriaux A, Lakomy D, Sberna AL, Costa A, Bessede G, Athias
A, Steinmetz E, Lobaccaro JM, Alves G, Menicacci A, Vachenc S, Solary E, Gambert P,
Masson D. Induction of transglutaminase 2 by a liver X receptor/retinoic acid receptor
alpha pathway increases the clearance of apoptotic cells by human macrophages. Circ
Res 105: 393– 401, 2009.
426. Reichel H, Koeffler HP, Barbers R, Norman AW. Regulation of 1,25-dihydroxyvitamin
D3 production by cultured alveolar macrophages from normal human donors and
from patients with pulmonary sarcoidosis. J Clin Endocrinol Metab 65: 1201–1209,
1987.
427. Reichel H, Koeffler HP, Bishop JE, Norman AW. 25-Hydroxyvitamin D3 metabolism
by lipopolysaccharide-stimulated normal human macrophages. J Clin Endocrinol Metab
64: 1–9, 1987.
428. Reichel H, Koeffler HP, Norman AW. Synthesis in vitro of 1,25-dihydroxyvitamin D3
and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone
marrow and alveolar macrophages. J Biol Chem 262: 10931–10937, 1987.
429. Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in
health and disease. N Engl J Med 320: 980 –991, 1989.
430. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol 6: 476 – 483, 2006.
410. Petkovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which
belongs to the family of nuclear receptors. Nature 330: 444 – 450, 1987.
431. Reis e Sousa C. Toll-like receptors and dendritic cells: for whom the bug tolls. Semin
Immunol 16: 27–34, 2004.
411. Phan TG, Grigorova I, Okada T, Cyster JG. Subcapsular encounter and complementdependent transport of immune complexes by lymph node B cells. Nat Immunol 8:
992–1000, 2007.
432. Reiss Y, Proudfoot AE, Power CA, Campbell JJ, Butcher EC. CC chemokine receptor
(CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in
lymphocyte trafficking to inflamed skin. J Exp Med 194: 1541–1547, 2001.
784
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
395. Oritani K, Kaisho T, Nakajima K, Hirano T. Retinoic acid inhibits interleukin-6-induced
macrophage differentiation and apoptosis in a murine hematopoietic cell line, Y6.
Blood 80: 2298 –2305, 1992.
NAGY ET AL.
433. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ. Regulation of
ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors
alpha and beta. J Biol Chem 277: 18793–18800, 2002.
434. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS,
Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding
protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes
Dev 14: 2819 –2830, 2000.
435. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA,
Dietschy JM, Mangelsdorf DJ. Regulation of absorption and ABC1-mediated efflux of
cholesterol by RXR heterodimers. Science 289: 1524 –1529, 2000.
436. Ricote M, Glass CK. PPARs and molecular mechanisms of transrepression. Biochim
Biophys Acta 1771: 926 –935, 2007.
437. Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W,
Glass CK. Expression of the peroxisome proliferator-activated receptor gamma
(PPARgamma) in human atherosclerosis and regulation in macrophages by colony
stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 95:
7614 –7619, 1998.
439. Ricote M, Snyder CS, Leung HY, Chen J, Chien KR, Glass CK. Normal hematopoiesis
after conditional targeting of RXRalpha in murine hematopoietic stem/progenitor
cells. J Leukoc Biol 80: 850 – 861, 2006.
440. Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1,25dihydroxyvitamin D3 (calcitriol). J Clin Invest 74: 1451–1455, 1984.
441. Rigby WF, Yirinec B, Oldershaw RL, Fanger MW. Comparison of the effects of 1,25dihydroxyvitamin D3 on T lymphocyte subpopulations. Eur J Immunol 17: 563–566,
1987.
442. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 66: 5314 –5321,
1998.
443. Rolph MS, Young TR, Shum BO, Gorgun CZ, Schmitz-Peiffer C, Ramshaw IA, Hotamisligil GS, Mackay CR. Regulation of dendritic cell function and T cell priming by the
fatty acid-binding protein AP2. J Immunol 177: 7794 –7801, 2006.
444. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, Stanford J. Vitamin D3,
gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57: 159 –163, 1986.
445. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM,
Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in
vivo and in vitro. Mol Cell 4: 611– 617, 1999.
446. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, Auwerx J, Metzger D,
Wahli W, Desvergne B, Naccari GC, Chavatte P, Farce A, Bulois P, Cortot A, Colombel JF, Desreumaux P. Intestinal antiinflammatory effect of 5-aminosalicylic acid is
dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 201:
1205–1215, 2005.
447. Russell DW. Nuclear orphan receptors control cholesterol catabolism. Cell 97: 539 –
542, 1999.
448. Russell DW. Oxysterol biosynthetic enzymes. Biochim Biophys Acta 1529: 126 –135,
2000.
449. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB,
Duverger N, Denefle P, Assmann G. Tangier disease is caused by mutations in the
gene encoding ATP-binding cassette transporter 1. Nat Genet 22: 352–355, 1999.
450. Sabol SL, Brewer HB Jr, Santamarina-Fojo S. The human ABCG1 gene: identification
of LXR response elements that modulate expression in macrophages and liver. J Lipid
Res 46: 2151–2167, 2005.
451. Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, Zugel U, Steinmeyer
A, Pollak A, Roth E, Boltz-Nitulescu G, Spittler A. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 36: 361–370, 2006.
453. Sandell LL, Sanderson BW, Moiseyev G, Johnson T, Mushegian A, Young K, Rey JP, Ma
JX, Staehling-Hampton K, Trainor PA. RDH10 is essential for synthesis of embryonic
retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev
21: 1113–1124, 2007.
454. Sarkadi B, Homolya L, Szakacs G, Varadi A. Human multidrug resistance ABCB and
ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev 86:
1179 –1236, 2006.
455. Saurer L, McCullough KC, Summerfield A. In vitro induction of mucosa-type dendritic
cells by all-trans retinoic acid. J Immunol 179: 3504 –3514, 2007.
456. Savina A, Amigorena S. Phagocytosis and antigen presentation in dendritic cells. Immunol Rev 219: 143–156, 2007.
457. Schaier M, Lehrke I, Schade K, Morath C, Shimizu F, Kawachi H, Grone HJ, Ritz E,
Wagner J. Isotretinoin alleviates renal damage in rat chronic glomerulonephritis. Kidney Int 60: 2222–2234, 2001.
458. Schaier M, Liebler S, Schade K, Shimizu F, Kawachi H, Grone HJ, Chandraratna R, Ritz
E, Wagner J. Retinoic acid receptor alpha and retinoid X receptor specific agonists
reduce renal injury in established chronic glomerulonephritis of the rat. J Mol Med 82:
116 –125, 2004.
459. Schebesch C, Kodelja V, Muller C, Hakij N, Bisson S, Orfanos CE, Goerdt S. Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4⫹ T cells in vitro. Immunology 92: 478 – 486, 1997.
460. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118: 2992–3002, 2008.
461. Schild RL, Schaiff WT, Carlson MG, Cronbach EJ, Nelson DM, Sadovsky Y. The
activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipids.
J Clin Endocrinol Metab 87: 1105–1110, 2002.
462. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M,
Mangelsdorf DJ, Lustig KD, Shan B. Role of LXRs in control of lipogenesis. Genes Dev
14: 2831–2838, 2000.
463. Schulz O, Pennington DJ, Hodivala-Dilke K, Febbraio M, Reis e Sousa C. CD36 or
alphavbeta3 and alphavbeta5 integrins are not essential for MHC class I cross-presentation of cell-associated antigen by CD8 alpha⫹ murine dendritic cells. J Immunol 168:
6057– 6065, 2002.
464. Schwartz K, Lawn RM, Wade DP. ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Commun 274: 794 – 802,
2000.
465. Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in
the development of multiple hematopoietic lineages. Science 265: 1573–1577, 1994.
466. Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection.
Immunity 19: 59 –70, 2003.
467. Serhan CN, Devchand PR. Novel antiinflammatory targets for asthma. A role for
PPARgamma? Am J Respir Cell Mol Biol 24: 658 – 661, 2001.
468. Sevov M, Elfineh L, Cavelier LB. Resveratrol regulates the expression of LXR-alpha in
human macrophages. Biochem Biophys Res Commun 348: 1047–1054, 2006.
469. Shah YM, Morimura K, Gonzalez FJ. Expression of peroxisome proliferator-activated
receptor-gamma in macrophage suppresses experimentally induced colitis. Am J
Physiol Gastrointest Liver Physiol 292: G657–G666, 2007.
470. Shiohara M, Dawson MI, Hobbs PD, Sawai N, Higuchi T, Koike K, Komiyama A,
Koeffler HP. Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic
proliferation and differentiation in vitro. Blood 93: 2057–2066, 1999.
471. Shirakawa AK, Nagakubo D, Hieshima K, Nakayama T, Jin Z, Yoshie O. 1,25-dihydroxyvitamin D3 induces CCR10 expression in terminally differentiating human B
cells. J Immunol 180: 2786 –2795, 2008.
472. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 116:
1793–1801, 2006.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
785
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
438. Ricote M, Huang JT, Welch JS, Glass CK. The peroxisome proliferator-activated
receptor (PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc
Biol 66: 733–739, 1999.
452. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human
dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor
plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179:
1109 –1118, 1994.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
473. Shulman AI, Mangelsdorf DJ. Retinoid x receptor heterodimers in the metabolic
syndrome. N Engl J Med 353: 604 – 615, 2005.
474. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC. DCs
metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol 8: 285–293, 2007.
475. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J.
Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature
417: 750 –754, 2002.
476. Sly LM, Lopez M, Nauseef WM, Reiner NE. 1alpha,25-Dihydroxyvitamin D3-induced
monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and
mediated by the NADPH-dependent phagocyte oxidase. J Biol Chem 276: 35482–
35493, 2001.
493. Sunaga S, Maki K, Lagasse E, Blanco JC, Ozato K, Miyazaki J, Ikuta K. Myeloid differentiation is impaired in transgenic mice with targeted expression of a dominant negative form of retinoid X receptor beta. Br J Haematol 96: 19 –30, 1997.
494. Svensson M, Marsal J, Ericsson A, Carramolino L, Broden T, Marquez G, Agace WW.
CCL25 mediates the localization of recently activated CD8alphabeta(⫹) lymphocytes
to the small-intestinal mucosa. J Clin Invest 110: 1113–1121, 2002.
495. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P,
Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby
P, Weissleder R, Pittet MJ. Identification of splenic reservoir monocytes and their
deployment to inflammatory sites. Science 325: 612– 616, 2009.
496. Szabo E, Preis LH, Birrer MJ. Constitutive cJun expression induces partial macrophage
differentiation in U-937 cells. Cell Growth Differ 5: 439 – 446, 1994.
497. Szanto A, Balint BL, Nagy ZS, Barta E, Dezso B, Pap A, Szeles L, Poliska S, Oros M,
Evans RM, Barak Y, Schwabe J, Nagy L. STAT6 transcription factor is a facilitator of the
nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity 33: 699 –712, 2010.
478. Solomin L, Johansson CB, Zetterstrom RH, Bissonnette RP, Heyman RA, Olson L,
Lendahl U, Frisen J, Perlmann T. Retinoid-X receptor signalling in the developing
spinal cord. Nature 395: 398 – 402, 1998.
498. Szanto A, Benko S, Szatmari I, Balint BL, Furtos I, Ruhl R, Molnar S, Csiba L, Garuti R,
Calandra S, Larsson H, Diczfalusy U, Nagy L. Transcriptional regulation of human
CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X
receptor signaling in macrophages. Mol Cell Biol 24: 8154 – 8166, 2004.
479. Song C, Hiipakka RA, Kokontis JM, Liao S. Ubiquitous receptor: structures, immunocytochemical localization, modulation of gene activation by receptors for retinoic
acids and thyroid hormones. Ann NY Acad Sci 761: 38 – 49, 1995.
480. Sorg BL, Klan N, Seuter S, Dishart D, Radmark O, Habenicht A, Carlberg C, Werz O,
Steinhilber D. Analysis of the 5-lipoxygenase promoter and characterization of a
vitamin D receptor binding site. Biochim Biophys Acta 1761: 686 – 697, 2006.
481. Spears M, McSharry C, Thomson NC. Peroxisome proliferator-activated receptorgamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy 36: 1494 –1504, 2006.
482. Standiford TJ, Kunkel SL, Liebler JM, Burdick MD, Gilbert AR, Strieter RM. Gene
expression of macrophage inflammatory protein-1 alpha from human blood monocytes and alveolar macrophages is inhibited by interleukin-4. Am J Respir Cell Mol Biol
9: 192–198, 1993.
483. Steffensen KR, Schuster GU, Parini P, Holter E, Sadek CM, Cassel T, Eskild W,
Gustafsson JA. Different regulation of the LXRalpha promoter activity by isoforms of
CCAAT/enhancer-binding proteins. Biochem Biophys Res Commun 293: 1333–1340,
2002.
499. Szanto A, Nagy L. Retinoids potentiate peroxisome proliferator-activated receptor
gamma action in differentiation, gene expression, lipid metabolic processes in developing myeloid cells. Mol Pharmacol 67: 1935–1943, 2005.
500. Szanto A, Nagy L. The many faces of PPARgamma: anti-inflammatory by any means?
Immunobiology 213: 789 – 803, 2008.
501. Szanto A, Roszer T. Nuclear receptors in macrophages: a link between metabolism
and inflammation. FEBS Lett 582: 106 –116, 2008.
502. Szatmari I, Gogolak P, Im JS, Dezso B, Rajnavolgyi E, Nagy L. Activation of PPARgamma specifies a dendritic cell subtype capable of enhanced induction of iNKT cell
expansion. Immunity 21: 95–106, 2004.
503. Szatmari I, Nagy L. Nuclear receptor signalling in dendritic cells connects lipids, the
genome and immune function. EMBO J 27: 2353–2362, 2008.
504. Szatmari I, Pap A, Ruhl R, Ma JX, Illarionov PA, Besra GS, Rajnavolgyi E, Dezso B, Nagy
L. PPARgamma controls CD1d expression by turning on retinoic acid synthesis in
developing human dendritic cells. J Exp Med 203: 2351–2362, 2006.
484. Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine
macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176: 287–292, 1992.
505. Szatmari I, Torocsik D, Agostini M, Nagy T, Gurnell M, Barta E, Chatterjee K, Nagy L.
PPARgamma regulates the function of human dendritic cells primarily by altering lipid
metabolism. Blood 110: 3271–3280, 2007.
485. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol.
Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med
320: 915–924, 1989.
506. Szatmari I, Vamosi G, Brazda P, Balint BL, Benko S, Szeles L, Jeney V, Ozvegy-Laczka
C, Szanto A, Barta E, Balla J, Sarkadi B, Nagy L. Peroxisome proliferator-activated
receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells. J Biol Chem 281: 23812–23823, 2006.
486. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 449: 419 –
426, 2007.
487. Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid
organs of mice. I. Morphology, quantitation, and tissue distribution. J Exp Med 137:
1142–1162, 1973.
488. Stock A, Booth S, Cerundolo V. Prostaglandin E2 suppresses the differentiation of
retinoic acid-producing dendritic cells in mice and humans. J Exp Med 208: 761–773,
2011.
489. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, Sengchanthalangsy LL,
Ghosh G, Glass CK. 15-Deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in
the NF-kappa B signaling pathway. Proc Natl Acad Sci USA 97: 4844 – 4849, 2000.
490. Sucov HM, Dyson E, Gumeringer CL, Price J, Chien KR, Evans RM. RXR alpha mutant
mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes
Dev 8: 1007–1018, 1994.
507. Szeles L, Keresztes G, Torocsik D, Balajthy Z, Krenacs L, Poliska S, Steinmeyer A,
Zuegel U, Pruenster M, Rot A, Nagy L. 1,25-Dihydroxyvitamin D3 is an autonomous
regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype. J Immunol 182: 2074 –2083, 2009.
508. Szeles L, Poliska S, Nagy G, Szatmari I, Szanto A, Pap A, Lindstedt M, Santegoets SJ,
Ruhl R, Dezso B, Nagy L. Research resource: transcriptome profiling of genes regulated by RXR and its permissive and nonpermissive partners in differentiating monocyte-derived dendritic cells. Mol Endocrinol 24: 2218 –2231, 2010.
509. Szondy Z, Sarang Z, Molnar P, Nemeth T, Piacentini M, Mastroberardino PG, Falasca
L, Aeschlimann D, Kovacs J, Kiss I, Szegezdi E, Lakos G, Rajnavolgyi E, Birckbichler PJ,
Melino G, Fesus L. Transglutaminase 2⫺/⫺ mice reveal a phagocytosis-associated
crosstalk between macrophages and apoptotic cells. Proc Natl Acad Sci USA 100:
7812–7817, 2003.
491. Sucov HM, Evans RM. Retinoic acid and retinoic acid receptors in development. Mol
Neurobiol 10: 169 –184, 1995.
510. Takeda N, Manabe I, Shindo T, Iwata H, Iimuro S, Kagechika H, Shudo K, Nagai R.
Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis
in mice by inhibiting IL-6. Arterioscler Thromb Vasc Biol 26: 1177–1183, 2006.
492. Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. Small intestine
lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via
retinoic acid. J Exp Med 2007.
511. Takeuchi A, Reddy GS, Kobayashi T, Okano T, Park J, Sharma S. Nuclear factor of
activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3mediated effects. J Immunol 160: 209 –218, 1998.
786
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
477. Smeland EB, Rusten L, Jacobsen SE, Skrede B, Blomhoff R, Wang MY, Funderud S,
Kvalheim G, Blomhoff HK. All-trans retinoic acid directly inhibits granulocyte colonystimulating factor-induced proliferation of CD34⫹ human hematopoietic progenitor
cells. Blood 84: 2940 –2945, 1994.
NAGY ET AL.
512. Talukdar S, Hillgartner FB. The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0 –
901317. J Lipid Res 47: 2451–2461, 2006.
513. Tao Y, Yang Y, Wang W. Effect of all-trans-retinoic acid on the differentiation, maturation and functions of dendritic cells derived from cord blood monocytes. FEMS
Immunol Med Microbiol 47: 444 – 450, 2006.
514. Tarrade A, Schoonjans K, Guibourdenche J, Bidart JM, Vidaud M, Auwerx J, RochetteEgly C, Evain-Brion D. PPAR gamma/RXR alpha heterodimers are involved in human
CG beta synthesis and human trophoblast differentiation. Endocrinology 142: 4504 –
4514, 2001.
515. Tarrade A, Schoonjans K, Pavan L, Auwerx J, Rochette-Egly C, Evain-Brion D,
Fournier T. PPARgamma/RXRalpha heterodimers control human trophoblast invasion. J Clin Endocrinol Metab 86: 5017–5024, 2001.
516. Terasaka N, Hiroshima A, Koieyama T, Ubukata N, Morikawa Y, Nakai D, Inaba T.
T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett 536: 6 –11, 2003.
518. Tocci A, Parolini I, Gabbianelli M, Testa U, Luchetti L, Samoggia P, Masella B, Russo G,
Valtieri M, Peschle C. Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/
erythroid/monocytic to granulocytic differentiation program. Blood 88: 2878 –2888,
1996.
533. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves
DR, Murray PJ, Chawla A. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4: 13–24, 2006.
534. Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3)
receptor in the immune system. Arch Biochem Biophys 374: 334 –338, 2000.
535. Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, Tontonoz P. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR
alpha. Proc Natl Acad Sci USA 97: 12097–12102, 2000.
536. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, Edwards PA.
Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 275: 14700 –14707,
2000.
537. Villa R, Pasini D, Gutierrez A, Morey L, Occhionorelli M, Vire E, Nomdedeu JF,
Jenuwein T, Pelicci PG, Minucci S, Fuks F, Helin K, Di Croce L. Role of the polycomb
repressive complex 2 in acute promyelocytic leukemia. Cancer Cell 11: 513–525,
2007.
538. Villablanca EJ, Raccosta L, Zhou D, Fontana R, Maggioni D, Negro A, Sanvito F,
Ponzoni M, Valentinis B, Bregni M, Prinetti A, Steffensen KR, Sonnino S, Gustafsson JA,
Doglioni C, Bordignon C, Traversari C, Russo V. Tumor-mediated liver X receptoralpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and
dampens antitumor responses. Nat Med 16: 98 –105, 2010.
519. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissuespecific regulator of an adipocyte enhancer. Genes Dev 8: 1224 –1234, 1994.
539. Villablanca EJ, Zhou D, Valentinis B, Negro A, Raccosta L, Mauri L, Prinetti A, Sonnino
S, Bordignon C, Traversari C, Russo V. Selected natural and synthetic retinoids impair
CCR7- and CXCR4-dependent cell migration in vitro and in vivo. J Leukoc Biol 84:
871– 879, 2008.
520. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes
monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93: 241–252,
1998.
540. Villadangos JA, Heath WR. Life cycle, migration and antigen presenting functions of
spleen and lymph node dendritic cells: limitations of the Langerhans cells paradigm.
Semin Immunol 17: 262–272, 2005.
521. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma.
Annu Rev Biochem 77: 289 –312, 2008.
522. Torocsik D, Barath M, Benko S, Szeles L, Dezso B, Poliska S, Hegyi Z, Homolya L,
Szatmari I, Lanyi A, Nagy L. Activation of liver X receptor sensitizes human dendritic
cells to inflammatory stimuli. J Immunol 184: 5456 –5465 2010.
523. Torocsik D, Szanto A, Nagy L. Oxysterol signaling links cholesterol metabolism and
inflammation via the liver X receptor in macrophages. Mol Aspects Med 30: 134 –152,
2009.
524. Tsai S, Bartelmez S, Heyman R, Damm K, Evans R, Collins SJ. A mutated retinoic acid
receptor-alpha exhibiting dominant-negative activity alters the lineage development
of a multipotent hematopoietic cell line. Genes Dev 6: 2258 –2269, 1992.
525. Tsai S, Collins SJ. A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage. Proc Natl Acad Sci USA 90: 7153–7157, 1993.
526. Turner RT, Bottemiller BL, Howard GA, Baylink DJ. In vitro metabolism of 25hydroxyvitamin D3 by isolated rat kidney cells. Proc Natl Acad Sci USA 77: 1537–1540,
1980.
527. Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ, Nishiyama M, Sato S, Tsujimura
T, Yamamoto M, Yokota Y, Kiyono H, Miyasaka M, Ishii KJ, Akira S. Regulation of
humoral and cellular gut immunity by lamina propria dendritic cells expressing Tolllike receptor 5. Nat Immunol 9: 769 –776, 2008.
528. Umesono K, Murakami KK, Thompson CC, Evans RM. Direct repeats as selective
response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors.
Cell 65: 1255–1266, 1991.
529. Unanue ER. Antigen-presenting function of the macrophage. Annu Rev Immunol 2:
395– 428, 1984.
530. Uppenberg J, Svensson C, Jaki M, Bertilsson G, Jendeberg L, Berkenstam A. Crystal
structure of the ligand binding domain of the human nuclear receptor PPARgamma. J
Biol Chem 273: 31108 –31112, 1998.
531. Valledor AF, Hsu LC, Ogawa S, Sawka-Verhelle D, Karin M, Glass CK. Activation of
liver X receptors and retinoid X receptors prevents bacterial-induced macrophage
apoptosis. Proc Natl Acad Sci USA 101: 17813–17818, 2004.
541. Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of
dendritic-cell subsets in vivo. Nat Rev Immunol 7: 543–555, 2007.
542. Vivat-Hannah V, Bourguet W, Gottardis M, Gronemeyer H. Separation of retinoid X
receptor homo- and heterodimerization functions. Mol Cell Biol 23: 7678 –7688,
2003.
543. Wada Y, Hisamatsu T, Kamada N, Okamoto S, Hibi T. Retinoic acid contributes to the
induction of IL-12-hypoproducing dendritic cells. Inflamm Bowel Dis 2009.
544. Waku T, Shiraki T, Oyama T, Fujimoto Y, Maebara K, Kamiya N, Jingami H, Morikawa
K. Structural insight into PPARgamma activation through covalent modification with
endogenous fatty acids. J Mol Biol 385: 188 –199, 2009.
545. Walkley CR, Purton LE, Snelling HJ, Yuan YD, Nakajima H, Chambon P, Chandraratna
RA, McArthur GA. Identification of the molecular requirements for an RAR alphamediated cell cycle arrest during granulocytic differentiation. Blood 103: 1286 –1295,
2004.
546. Wang K, Wang P, Shi J, Zhu X, He M, Jia X, Yang X, Qiu F, Jin W, Qian M, Fang H, Mi
J, Xiao H, Minden M, Du Y, Chen Z, Zhang J. PML/RARalpha targets promoter regions
containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia.
Cancer Cell 17: 186 –197, 2010.
547. Wang TT, Dabbas B, Laperriere D, Bitton AJ, Soualhine H, Tavera-Mendoza LE,
Dionne S, Servant MJ, Bitton A, Seidman EG, Mader S, Behr MA, White JH. Direct and
indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin
beta2 innate immune pathway defective in Crohn disease. J Biol Chem 285: 2227–
2231, 2010.
548. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R,
Hanrahan JW, Mader S, White JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct
inducer of antimicrobial peptide gene expression. J Immunol 173: 2909 –2912, 2004.
549. Wang X, Allen C, Ballow M. Retinoic acid enhances the production of IL-10 while
reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J Clin Immunol 27: 193–200, 2007.
550. Wang X, Scott E, Sawyers CL, Friedman AD. C/EBPalpha bypasses granulocyte colony-stimulating factor signals to rapidly induce PU.1 gene expression, stimulate gran-
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
787
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
517. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes
PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski
PJ, Bloom BR, Modlin RL. Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291: 1544 –1547, 2001.
532. Van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 97: 93–101, 2005.
NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES
ulocytic differentiation, and limit proliferation in 32D cl3 myeloblasts. Blood 94: 560 –
571, 1999.
551. Wang Y, Kurdi-Haidar B, Oram JF. LXR-mediated activation of macrophage stearoylCoA desaturase generates unsaturated fatty acids that destabilize ABCA1. J Lipid Res
45: 972–980, 2004.
552. Wang Y, Zhang JJ, Dai W, Pike JW. Production of granulocyte colony-stimulating
factor by THP-1 cells in response to retinoic acid and phorbol ester is mediated
through the autocrine production of interleukin-1. Biochem Biophys Res Commun 225:
639 – 646, 1996.
553. Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, Grosveld F,
Pandolfi PP. Role of PML in cell growth and the retinoic acid pathway. Science 279:
1547–1551, 1998.
554. Ward JE, Tan X. Peroxisome proliferator activated receptor ligands as regulators of
airway inflammation and remodelling in chronic lung disease. PPAR Res 2007: 14983,
2007.
556. Warrell RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of
transcription in acute promyelocytic leukemia by use of an inhibitor of histone
deacetylase. J Natl Cancer Inst 90: 1621–1625, 1998.
557. Weber C, Belge KU, von Hundelshausen P, Draude G, Steppich B, Mack M, Frankenberger M, Weber KS, Ziegler-Heitbrock HW. Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol 67: 699 –704,
2000.
558. Wei LN, Farooqui M, Hu X. Ligand-dependent formation of retinoid receptors, receptor-interacting protein 140 (RIP140), and histone deacetylase complex is mediated by a novel receptor-interacting motif of RIP140. J Biol Chem 276: 16107–16112,
2001.
559. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL,
Ferrante AW Jr. CCR2 modulates inflammatory and metabolic effects of high-fat
feeding. J Clin Invest 116: 115–124, 2006.
560. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity
is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796 –
1808, 2003.
561. Welch JS, Ricote M, Akiyama TE, Gonzalez FJ, Glass CK. PPARgamma and PPARdelta
negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target
genes in macrophages. Proc Natl Acad Sci USA 100: 6712– 6717, 2003.
562. Whitney KD, Watson MA, Goodwin B, Galardi CM, Maglich JM, Wilson JG, Willson
TM, Collins JL, Kliewer SA. Liver X receptor (LXR) regulation of the LXRalpha gene
in human macrophages. J Biol Chem 276: 43509 – 43515, 2001.
563. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M,
Davidson RN. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.
Lancet 355: 618 – 621, 2000.
564. Willy PJ, Mangelsdorf DJ. Unique requirements for retinoid-dependent transcriptional
activation by the orphan receptor LXR. Genes Dev 11: 289 –298, 1997.
565. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a
nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9:
1033–1045, 1995.
566. Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced
by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times
during gestation. Am J Anat 92: 189 –217, 1953.
567. Wilson NS, Villadangos JA. Lymphoid organ dendritic cells: beyond the Langerhans
cells paradigm. Immunol Cell Biol 82: 91–98, 2004.
568. Winzler C, Rovere P, Rescigno M, Granucci F, Penna G, Adorini L, Zimmermann VS,
Davoust J, Ricciardi-Castagnoli P. Maturation stages of mouse dendritic cells in growth
factor-dependent long-term cultures. J Exp Med 185: 317–328, 1997.
788
570. Wu L, Liu YJ. Development of dendritic-cell lineages. Immunity 26: 741–750, 2007.
571. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS,
Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112: 1821–1830, 2003.
572. Xu H, Soruri A, Gieseler RK, Peters JH. 1,25-Dihydroxyvitamin D3 exerts opposing
effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol 38: 535–540, 1993.
573. Yamada H, Mizuno S, Ross AC, Sugawara I. Retinoic acid therapy attenuates the
severity of tuberculosis while altering lymphocyte and macrophage numbers and
cytokine expression in rats infected with Mycobacterium tuberculosis. J Nutr 137:
2696 –2700, 2007.
574. Yamanaka K, Dimitroff CJ, Fuhlbrigge RC, Kakeda M, Kurokawa I, Mizutani H, Kupper
TS. Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J Allergy Clin Immunol 121: 148 –157 e143, 2008.
575. Yamanaka R, Kim GD, Radomska HS, Lekstrom-Himes J, Smith LT, Antonson P,
Tenen DG, Xanthopoulos KG. CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is
determined by alternative use of promoters and differential splicing. Proc Natl Acad Sci
USA 94: 6462– 6467, 1997.
576. Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goddard A, Wood WI,
Gurney AL, Godowski PJ. Toll-like receptor-2 mediates lipopolysaccharide-induced
cellular signalling. Nature 395: 284 –288, 1998.
577. Yeh K, Silberman D, Gonzalez D, Riggs J. Complementary suppression of T cell
activation by peritoneal macrophages and CTLA-4-Ig. Immunobiology 212: 1–10,
2007.
578. Yokota A, Takeuchi H, Maeda N, Ohoka Y, Kato C, Song SY, Iwata M. GM-CSF and
IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity.
Int Immunol 21: 361–377, 2009.
579. Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T,
Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S,
Ishibashi S, Yamada N. Identification of liver X receptor-retinoid X receptor as an
activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell
Biol 21: 2991–3000, 2001.
580. Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T,
Arioka K, Sato H, Uchiyama Y, Masushige S, Fukamizu A, Matsumoto T, Kato S. Mice
lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia
and growth retardation after weaning. Nat Genet 16: 391–396, 1997.
581. Yu K, Bayona W, Kallen CB, Harding HP, Ravera CP, McMahon G, Brown M, Lazar
MA. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem 270: 23975–23983, 1995.
582. Yu L, Cao G, Repa J, Stangl H. Sterol regulation of scavenger receptor class B type I in
macrophages. J Lipid Res 45: 889 – 899, 2004.
583. Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development.
Proc Natl Acad Sci USA 105: 5207–5212, 2008.
584. Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin
JM, Glass CK, Rosenfeld MG. RXR beta: a coregulator that enhances binding of
retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response
elements. Cell 67: 1251–1266, 1991.
585. Zapata-Gonzalez F, Rueda F, Petriz J, Domingo P, Villarroya F, de Madariaga A,
Domingo JC. 9-cis-Retinoic acid (9cRA), a retinoid X receptor (RXR) ligand, exerts
immunosuppressive effects on dendritic cells by RXR-dependent activation: inhibition
of peroxisome proliferator-activated receptor gamma blocks some of the 9cRA activities, precludes them to mature phenotype development. J Immunol 178: 6130 –
6139, 2007.
586. Zapata-Gonzalez F, Rueda F, Petriz J, Domingo P, Villarroya F, Diaz-Delfin J, de
Madariaga MA, Domingo JC. Human dendritic cell activities are modulated by the
omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR(gamma):RXR heterodimers: comparison with other polyunsaturated fatty acids. J Leukoc Biol 84: 1172–
1182, 2008.
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
555. Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN,
Vyas R, Andreeff M, Tafuri A, Jakubowski A. Differentiation therapy of acute
promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 324:
1385–1393, 1991.
569. Wong KL, Tai JJ, Wong WC, Han H, Sem X, Yeap WH, Kourilsky P, Wong SC. Gene
expression profiling reveals the defining features of the classical, intermediate, and
nonclassical human monocyte subsets. Blood 118: e16 – e31, 2011.
NAGY ET AL.
587. Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake
through Idol-dependent ubiquitination of the LDL receptor. Science 325: 100 –
104, 2009.
591. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ. Regulation of lipoprotein lipase by
the oxysterol receptors, LXRalpha and LXRbeta. J Biol Chem 276: 43018 – 43024,
2001.
588. Zenke M, Hieronymus T. Towards an understanding of the transcription
factor network of dendritic cell development. Trends Immunol 27: 140 –145,
2006.
592. Zhu J, Emerson SG. Hematopoietic cytokines, transcription factors and lineage commitment. Oncogene 21: 3295–3313, 2002.
589. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Absence
of granulocyte colony-stimulating factor signaling and neutrophil development in
CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA 94:
569 –574, 1997.
590. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM, Shigematsu
H, Levantini E, Huettner CS, Lekstrom-Himes JA, Akashi K, Tenen DG. Enhancement
of hematopoietic stem cell repopulating capacity and self-renewal in the absence of
the transcription factor C/EBP alpha. Immunity 21: 853– 863, 2004.
593. Zhu J, Heyworth CM, Glasow A, Huang QH, Petrie K, Lanotte M, Benoit G, Gallagher
R, Waxman S, Enver T, Zelent A. Lineage restriction of the RARalpha gene expression
in myeloid differentiation. Blood 98: 2563–2567, 2001.
594. Zhu L, Bisgaier CL, Aviram M, Newton RS. 9-Cis retinoic acid induces monocyte
chemoattractant protein-1 secretion in human monocytic THP-1 cells. Arterioscler
Thromb Vasc Biol 19: 2105–2111, 1999.
595. Ziegler-Heitbrock L. The CD14⫹ CD16⫹ blood monocytes: their role in infection
and inflammation. J Leukoc Biol 81: 584 –592, 2007.
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017
Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org
789