Download Polarization of the Innate Immune Response by Prostaglandin E2: A

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MOLECULAR PHARMACOLOGY
Copyright ª 2013 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/mol.113.089573
Mol Pharmacol 85:187–197, January 2014
MINIREVIEW
Polarization of the Innate Immune Response by Prostaglandin
E2: A Puzzle of Receptors and Signals
Mario Rodríguez, Esther Domingo, Cristina Municio, Yolanda Alvarez, Etzel Hugo,
Nieves Fernández, and Mariano Sánchez Crespo
Received September 11, 2013; accepted October 29, 2013
ABSTRACT
Eicosanoids tailor the innate immune response by supporting
local inflammation and exhibiting immunomodulatory properties. Prostaglandin (PG) E2 is the most abundant eicosanoid in
the inflammatory milieu due to the robust production elicited by
pathogen-associated molecular patterns on cells of the innate
immune system. The different functions and cell distribution of E
prostanoid receptors explain the difficulty encountered thus far
to delineate the actual role of PGE2 in the immune response. The
biosynthesis of eicosanoids includes as the first step the Ca21and kinase-dependent activation of the cytosolic phospholipase
A2, which releases arachidonic acid from membrane phospholipids, and later events depending on the transcriptional regulation of the enzymes of the cyclooxygenase routes, where
PGE2 is the most relevant product. Acting in an autocrine/
paracrine manner in macrophages, PGE2 induces a regulatory
Introduction
Eicosanoids are molecules derived from the oxidative
metabolism of arachidonic acid (AA) that display numerous
functions in organ homeostasis, including reproduction,
hemostasis, acute inflammation, allergy, and pain. Their
roles in inflammation at the site of pathogen entry and in IgEmediated reactions have been the focus of intensive study.
More recently, it has been underscored that some eicosanoids
This work was supported by the Plan Nacional de Salud y Farmacia [Grant
SAF2010-15070]; Junta de Castilla y León [Grant CSI003A11-2]; Fundación
Ramón Areces; and Red Temática de Investigación Cardiovascular from the
Instituto de Salud Carlos III.
dx.doi.org/10.1124/mol.113.089573.
phenotype including the expression of interleukin (IL)-10, sphingosine kinase 1, and the tumor necrosis factor family molecule
LIGHT. PGE2 also stabilizes the suppressive function of myeloidderived suppressor cells, inhibits the release of IL-12 p70 by
macrophages and dendritic cells, and may enhance the production of IL-23. PGE2 is a central component of the inflammasomedependent induction of the eicosanoid storm that leads to
massive loss of intravascular fluid, increases the mortality rate
associated with coinfection by Candida ssp. and bacteria, and
inhibits fungal phagocytosis. These effects have important
consequences for the outcome of infections and the polarization of the immune response into the T helper cell types 2
and 17 and can be a clue to develop pharmacological tools
to address infectious, autoimmune, and autoinflammatory
diseases.
are involved in the induction of the immune response after
immunization, in the control of the activation of cytotoxic
T lymphocyte and T helper (Th)1–mediated responses, and in
the polarization of the immune response into Th2 and Th17
types. This diversity of actions makes it necessary to distinguish
the effects of the different compounds and the environmental
context in which they are produced. The first classification
of eicosanoids stems from their production in either the
lipoxygenase or the cyclooxygenase (COX) routes. Leukotrienes
(LTs) and lipoxins are the main products of the lipoxygenase
route, whereas thromboxanes and prostaglandins (PGs), with
PGE2 as the most relevant element, are the main COX products involved in the inflammatory response. The function of
ABBREVIATIONS: AA, arachidonic acid; BCL10, B-cell CLL/lymphoma 10; CARD9, caspase recruitment domain–containing protein 9; C/EBPb,
CCAAT/enhancer-binding protein b; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; CREB, cAMP response element-binding protein; CRTC,
CREB-regulated transcriptional coactivator; DC, dendritic cell; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin;
EP, E prostanoid; EPAC, exchange protein activated by cAMP; IFN, interferon; IKK, IkB kinase; IL, interleukin; ITAM, immunoreceptor tyrosine-based
activation motif; LPS, lipopolysaccharide; LT, leukotriene; MALT, mucose-associated lymphoid tissue; MAPK, mitogen-activated protein kinase; MDSC,
myeloid-derived suppressor cell; MRT67307, N-[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide; NF-kB, nuclear factor kB; PAMP, pathogen-associated molecular pattern; PG, prostaglandin; PGES, prostaglandin E synthase; PKA, protein
kinase A; PLC, phospholipase C; PRR, pattern recognition receptor; SIK, salt-inducible kinase; SYK, spleen tyrosine kinase; Th, T helper; TNFa, tumor
necrosis factor-a; TORC, transducer of regulated CREB activity; TLR, Toll-like receptor; TRAF6, TNF receptor-associated factor-6.
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Department of Biochemistry and Molecular Biology, University of Valladolid, Valladolid, Spain (M.R., N.F.); and Institute of
Biology and Molecular Genetics, Spanish National Research Council, Valladolid, Spain (E.D., C.M., Y.A., E.H., M.S.C.)
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stage in view of their capacity to interact with carbohydrate-based
structural signatures expressed in microbial cell walls (see
Geijtenbeek and Gringhuis, 2009, for a review). Signaling
through Toll-like receptors (TLRs) leads to the activation of
the mitogen-activated protein kinase (MAPK) cascade, IkB
kinase (IKK), the nuclear factor kB (NF-kB) family of
transcription factors, tank-binding kinase-1, and interferon
(IFN) regulatory factors. Nucleotide-binding oligomerization
domain family protein–like receptors are associated with
IKK and inflammasome activation that allows the caspase1–mediated processing of prointerleukin (IL)-1b and pro–IL-18
to fully active proteins. The C-type lectin receptors may induce
rapid responses because they contain immunoreceptor tyrosinebased activation motifs (ITAMs) that initiate a cascade of protein tyrosine phosphorylation reactions, phospholipase C (PLC)g
activation, Ca21 mobilization, and IKK activation (Fig. 1).
These features make signaling trough C-type lectin receptors
a unique paradigm for a comprehensive study of eicosanoid
production in the innate immune response.
Fig. 1. The Candida paradigm for AA metabolism in DCs. The mannan and b-glucan components of the fungal cell wall are recognized by at least
DC-SIGN, TLR2, dectin-1, the mannose receptor, and dectin-2. This gives rise to a series of signaling events implicating activation of SYK and Src families of
tyrosine kinases. Both routes converge to activate PLCg and through the generation of diacylglycerol activate protein kinase C and MAPK cascades.
Phosphorylation by MAPK and Ca2+-driven translocation of cPLA2a explain AA release from cell phospholipids. Activation of IkB kinases via MyD88 is
a major factor explaining COX-2 and PGES induction. The CARD9/MALT/BCL10/TRAF6 complex is also involved in the activation of IkB kinases. This
scheme has been constructed from the results reported by Suram et al. (2006, 2010), Valera et al. (2008), and Parti et al. (2010). DAG, diacylglycerol; IP3,
inositol 1,4,5-trisphosphate; IRAK, interleukin-1 receptor-associated kinase; MAL, MyD88 adaptor-like; P-Y, phosphotyrosine; ptgs2, COX-2 gene; mpges1,
microsomal prostaglandin E synthase-1 gene; TAK1, transforming growth factor-b–activated kinase-1.
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LTs in the pathogenesis of the immediate hypersensitivity
reactions elicited by allergens was most prominent from early
studies in sensitized tissues (Kellaway and Trethewie, 1940),
although at that time their chemical structure was unknown
and more than 3 decades were needed to unambiguously
characterize the activity that had been termed slow-reacting
substance of anaphylaxis with the cysteinyl-LTs C4, D4, and
E4 (Hammarström et al., 1979). Regarding the eicosanoids
released from phagocytes, it was necessary to wait for the
characterization of the receptors involved in the innate immune
response to ascertain their actual role in inflammation. In fact,
microbes have unique molecules termed pathogen-associated
molecular patterns (PAMPs) that are recognized through pattern
recognition receptors (PRRs) by the host innate immune system.
The Toll-like receptor family and the nucleotide-binding oligomerization domain family protein–like receptors (see Casanova
et al., 2011; Davis et al., 2011, respectively) are representative of
what Janeway (1989) first called PRRs. More recently, C-lectin
type receptors have enlarged the list of PRR and reached center
Eicosanoids in Innate Immunity
AA Release Is the Initial Step for Eicosanoid
Production
with an efficient substrate channeling model yielding AA for
PGE2 synthesis at the early stages of microbial ingestion and
explain the strong ability of b-glucans to fulfill the conditions
associated with acute release of AA and production of COX
products, in contrast to the effect of the TLR4 ligand LPS
that only elicits robust PGE2 production after COX-2 induction.
These findings also help explain the adjuvanticity associated
with b-glucans that is being used for vaccine technology
(Huang et al., 2010), since COX-2 activity is crucial for optimal
antibody response, especially when vaccines are poorly immunogenic (Ryan et al., 2006).
COX Enzymes and COX/Lipoxygenase
Cross-Talk
COX Enzymes. PGE2 is the predominant eicosanoid generated in response to TLR ligands, proinflammatory cytokines,
and fungal-derived PAMPs. Central to PGE2 production are
the COX enzymes, of which two isoforms exist that are
similar in structure and catalytic activity. COX-1 is a constitutive enzyme that is coupled to the cPLA2a and paves the
way for the production of PGE2 shortly after AA release. In
contrast, COX-2 is an inducible enzyme regulated at the
transcriptional level by an array of latent transcription factors that are activated downstream PRR engagement, namely
NF-kB, cAMP response element-binding protein (CREB),
CCAAT/enhancer-binding protein b (C/EBPb), and IFN regulatory factors. The relevance of post-transcriptional mechanisms that regulate mRNA stability and protein translation
have been disclosed in recent years, and include several proteins and microRNA that modulate the decay rate of ptgs2 (the
gene encoding COX-2) mRNA as well as two mechanisms of
protein degradation. Identification of multiple mRNA regulatory elements present within the ptgs2 39-untranslated region
was the first evidence suggesting that COX-2 might be regulated at a post-transcriptional level. This is explained by the
presence of adenylate- and uridylate-rich elements that interact with adenylate and uridylate binding proteins, such as
Hu antigen R, CUG triplet repeat–binding protein 2, T cell
intracellular antigen 1, tristetraprolin, RNA-binding motif
protein 3, and most recently Hsp70 (Kishor et al., 2013). With
regard to microRNA, miR-16, miR-101, miR-199, miR-143, and
miR-542-3p have shown to exhibit complementarity to adenylate- and uridylate-rich regions of ptgs2 that makes them
suitable to alter their mRNA stability (Dixon et al., 2013).
COX-2 protein has two independent routes of degradation:
endoplasmic reticulum–associated degradation and substratedependent degradation. N-Glycosylation of Asn594 leads to
entry of COX-2 into the endoplasmic reticulum–associated
degradation pathway. The second COX-2 degradation process
is substrate turnover dependent and is independent of
N-glycosylation at Asn594 (Wada et al., 2009). Notably, COX-2
protein stability has been found to be enhanced by atorvastatin,
which may influence dendritic cell (DC) function and counteract
some of the untoward effects associated with sustained inhibition of COX-2 (Alvarez et al., 2009b). COX enzymes control
PGE2 production by catalyzing the conversion of AA to PG in
a two-step process. First, hydrogen is abstracted from carbon 13
of AA. Then a molecule of oxygen is added to carbons 11 and 9,
thus provoking the cyclization and the addition of a second
molecule of oxygen to carbon 15 to generate PGG2. Second, the
hydroperoxide at carbon 15 of PGG2 is reduced to hydroxide by
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PLA2 catalyzes the release of fatty acids from the sn-2
position of phospholipids. There are 22 genes encoding PLA2 in
mammals that are usually grouped in three main types: the
secreted PLA2, the intracellular group VI calcium-independent
PLA2, and the group IV cytosolic PLA2. These structurally
diverse enzymes carry out distinct functional roles (Dennis
et al., 2011). The group IV cytosolic phospholipase A2 (cPLA2)
family includes the cPLA2a, PLA2b, and cPLA2g isoforms.
However, cPLA2a is the only PLA2 with specificity of AA and
its primary function is to mediate agonist-induced release of
AA. Because of its position as the upstream regulatory
enzyme for initiating production of bioactive lipid mediators,
cPLA2a has been considered a potentially important pharmacological target for the control of inflammatory responses.
cPLA2a is subject to post-translational mechanisms of regulation to ensure that the levels of free AA are tightly
controlled. These mechanisms include the following: 1) the
phosphorylation of Ser505-cPLA2 by MAPK in the catalytic
domain, which explains the increase of catalytic activity
elicited by cell agonists; and 2) Ca21-induced translocation
from the cytosol to membranes to allow cPLA2a interaction
with phospholipid substrate. cPLA2 phosphorylation was initially related to MAPK of the extracellular signal-regulated
kinase group (Lin et al., 1993), but the involvement of p38
MAPK was subsequently reported (Kramer et al., 1996). The
agonist-stimulated translocation is explained by a N-terminal
domain containing a 45 amino acid region with high homology
with the Ca21-dependent phospholipid binding motif expressed in protein kinase C and PLC (Clark et al., 1991). Due
to this structural feature, Ca 21 induces the translocation of
cPLA2a from the cytoplasm to the Golgi, endoplasmic reticulum,
and nuclear membrane. In keeping with this mechanism,
only agonists creating a sustained Ca21 influx are capable of
activating some elements of the AA cascade, such as the
5-lipoxygenase pathway, which are critically dependent on
Ca21 (Buczynski et al., 2007). Since activation of TLR4 by
lipopolysaccharide (LPS) fails to induce Ca21 transients
directly but elicits prostaglandin production in the absence
of lipoxygenase activation, a corollary to these findings is
that acute release of AA and long-term production of COX-2
metabolites are under the control of different signaling
pathways. Notably, PAMPs derived from the cellular wall of
fungi, the main component of which are b(1,3)-glucans, have
stood out as a class of stimuli able to activate both pathways.
This has pathophysiological relevance to understanding the
response of the host to infection by fungi such as Candida,
Cryptococcus, Aspergillus, and Pneumocystis jirovecii. The
recognition of b-glucans is carried out by the C-type lectin
receptor dectin-1 (clec7a gene) (Brown et al., 2002), which
contains an ITAM in its intracellular portion. Cross-linking
of this receptor allows activation of tyrosine kinases, including spleen tyrosine kinase (SYK), tyrosine phosphorylation of PLCg, and the elevation of the intracellular levels of
Ca21. In an elegant study stemming from the observation
that cPLA2a exhibits calcium-dependent targeting to the
endoplasmic reticulum, the site of COX localization, cPLA2a
and COX-2 were found to colocalize to the forming phagosome in mouse peritoneal macrophages uptaking the fungal
mimic zymosan (Girotti et al., 2004). These results fit well
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The Plasticity of Mononuclear Phagocytes
Explains Distinct Patterns of PGE2 Production
Opsonic and Nonopsonic Phagocytosis. Uptake of
phagocytosable particles and signaling from PRR depend on
both receptors that bind opsonic proteins and nonopsonic
receptors. This is relevant to the engulfment of bacteria and
fungi since these microbes can be coated by the complement
factor 3–derived protein iC3b and by opsonic IgG class
antibodies, which bind the integrin amb2/Mac-1 and FcgR
receptors, respectively. Among nonopsonic receptors, scavenger receptors and C-type lectin receptors are of special relevance to directly recognize PAMP expressed on the microbe
surface. Whereas the C-type lectin receptor dectin-1 recognizes b-glucans (Brown et al., 2002), dectin-2 recognizes
a-mannans (Sato et al., 2006), and DC-specific intercellular
adhesion molecule-3–grabbing nonintegrin (DC-SIGN) recognizes N-linked mannans (Cambi et al., 2008). The mannose
receptor recognizes terminal mannose and fucose residues,
but its ability to modulate cellular activation has not been
completely characterized (Martinez-Pomares, 2012). The
combinatorial usage of receptors for b-glucans and a-mannans makes it possible an efficient recognition of pathogen
dimorphic fungi since their cell wall contains an external
layer made up of mannose polymers and an underlying
layer of b-glucans. Cross-linking of opsonic receptors and
the nonopsonic receptors dectin-1 and dectin-2 allows the
recruitment of nonreceptor tyrosine kinases to the ITAMs
expressed either in the intracellular portion of the receptor or
in adaptor proteins, thus activating a cell signaling cascade
involving protein tyrosine phosphorylation reactions, PLCg
activation, Ca21 mobilization, and IKK activation. This diversity of receptors explains why signals elicited by a receptor
may be balanced by concomitant signals induced by associated PAMPs on the same microbe or from the environment. In
fact, the formation of the so-called phagocytic synapse is
a pivotal element to define the degree of response of the host
to the invading microbe, because recognition of PAMPs in
a particulate state is a critical checkpoint for scaling the
microbial threat versus the single recognition of soluble
PAMPs (Blander and Sander, 2012). Notably, the construction of this general paradigm for tailoring the host responses
stems from studies carried out with large b-glucan complexes,
in which the exclusion of inhibitory phosphatases from the
phagocytic synapse was a key element to start dectin-1–
coupled signaling (Goodridge et al., 2011).
The Different Macrophage Populations. Classic distinction between macrophage types includes the type M1
inflammatory macrophage and the M2 regulatory macrophage (see Sica and Mantovani, 2012 for a review). Peripheral
blood monocytes cultured in the presence of serum, a source of
macrophase colony-stimulating factor but not granulocyte
macrophage colony-stimulating factor (Vogt and Nathan,
2011), are considered nonpolarized macrophages (M0 type),
whereas the addition of different cytokine cocktails elicits
polarization versus the M1 or M2 type. For instance, the M1
type is induced by IFN-g and LPS, and the M2 type is induced
by IL-4 and IL-13. The ability of macrophages to produce
eicosanoids in response to some PAMPs is strongly dependent
on the type of polarization achieved and the ensuing pattern
of receptor expression. A central role for macrophage-derived
PGE2 in the induction of Th2 type immune responses has been
reported during the processing of particulate crystal-like
materials like alum and silica through a mechanism regulated by SYK and p38 MAPK. Under these conditions, the
production of PGE2 depends on receptor-independent particle
uptake and signaling from phagolysosomes, rather than on
the engagement of cell membrane receptors, and may occur in
the absence of inflammasome activation and IL-1b production
(Kuroda et al., 2011). These findings are reminiscent of the
response to other crystals such as sodium monourate particles
(Kool et al., 2011) and hemozoin (Shio et al., 2009), and also
agree with the reported activation of SYK by receptorindependent, direct membrane binding of monosodium urate
crystals in DCs (Ng et al., 2008). These results are in keeping
with the notion that particulate PAMPs are more active than
soluble PAMPs for scaling microbial threat and are relevant
to understand the inflammation induced by microcrystals. In
addition, they underscore the complexity of the process of
recognition of particles bearing PAMPs, which may include
receptor dependent and independent mechanisms, and is
influenced by receptor expression, the state of differentiation
of the cell, and the presence of molecules that affect receptor
function. Attempts to correlate the state of macrophage
differentiation with eicosanoid release have steadily shown
a predominant production of PGE2 and PGD2 and a varying
pattern of response dependent on the presence of costimulatory substances. For instance, growth factors such as macrophase colony-stimulating factor and granulocyte macrophage
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the peroxidase active site of COX to produce PGH2. PGH2 can be
converted to PGD2, PGE2, PGF2a, prostacyclin, or thromboxane
A2 by specific isomerases. PGE2 can be produced by three types
of prostaglandin E synthases (PGES): one cytosolic (cPGES)
and two membrane-associated (microsomal PGES-1 and -2).
mPGES-1 is induced by the same stimuli that induce COX-2. On
this basis, the combined induction of both COX-2 and mPGES-1
by proinflammatory stimuli explains the efficient conversion of
AA into PGE2.
COX/5-Lipoxygenase Cross-Talk. Cross-talk between
the 5-lipoxygenase route and the COX pathways was observed
in early studies by showing a widespread inhibitory effect of PG
on LT production. In addition to the marked effect of PGE2 in
DCs by inhibiting the expression of the 5-lipoxygenase–activating
protein that is required for the activity of 5-lipoxygenase (Harizi
et al., 2003), recent studies have disclosed new molecular
targets by showing that phosphorylation of cPLA2a enhances
its catalytic activity, whereas phosphorylation of LTC4 synthase is inhibitory. In a detailed study using zymosan as a
stimulus, inhibition of LTC4 synthase was preceded by the
production of PGE2 and abolished by aspirin treatment. This
effect was associated with activation of several types of receptors for PGE2, the major downstream signaling of which
were protein kinase A (PKA)–dependent phosphorylation reactions (Esser et al., 2011). A corollary to these findings is that
when COX routes are operative, tissues possess a negative
feedback mechanism to control the 5-lipoxygenase route. In the
particular case of the lung, where PGE2 exerts anti-inflammatory
effects and LTs drive inflammation, these findings provide
a mechanistic explanation for two relevant clinical situations
in asthma patients: the exacerbation of symptoms associated
with aspirin intolerance and the risks conferred by fungal
exposure in patients treated with high doses of nonsteroidal
anti-inflammatory drugs.
Eicosanoids in Innate Immunity
expressed on the surface of polymorphonuclears, monocytes,
and DCs, but DCs show the most robust responses. These
differential responses might be explained by several mechanisms: 1) expression in some myeloid cell types of an inhibitor
(e.g., tetraspanin CD37) that restricts dectin-1–CARD9 (caspase
recruitment domain–containing protein 9) signaling (Goodridge
et al., 2009); 2) gain of function of DCs by differentiation-induced
expression of a receptor cooperating with dectin-1; and 3)
induction along the process of differentiation of C-lectin receptor
isoforms supporting productive binding. The last two mechanisms seem most likely in view of the high level of alternative
exon splicing observed in dectin-1 and the current notion that
zymosan-induced AA requires cooperation with other C-type
lectin receptors, such as DC-SIGN, the expression of which is
enhanced during the differentiation of monocytes into DCs
(Domínguez-Soto et al., 2011). Altogether, these data indicate
that cooperative binding of particulate b-glucans and mannans
to C-type lectin receptors explains the activation of a cPLA2adependent route for AA release in DCs. Likewise, two
different routes are involved in the kB-driven induction of
COX-2 and the delayed production of PGE2 produced by
zymosan, the CARD9/mucose-associated lymphoid tissue
(MALT)/B-cell CLL/lymphoma 10 (BCL10)/TNF receptorassociated factor-6 (TRAF6) complex triggered by dectin-1
(Hara et al., 2007; LeibundGut-Landmann et al., 2007) and
TLR2-dependent activation of IkB kinases (Brown et al., 2003;
Gantner et al., 2003).
The Candida Paradigm for AA Release. The fungal
mimic zymosan has been used for many decades as a relevant
stimulus to study complement activation, phagocytosis, and
local inflammatory responses. On this basis, the results
observed using zymosan as a stimulus can be translated into
the context of clinical infection by fungi. This has been
confirmed in models using Candida and macrophages from
engineered mice to address AA release and PGE2 production.
Reports from the Leslie laboratory (Suram et al., 2006, 2010;
Parti et al., 2010) demonstrated that deletion of dectin-1
decreases the release of AA elicited by Candida albicans by
approximately 60%. MyD882/2 macrophages stimulated for 1
hour with C. albicans released approximately 50% less AA
than wild-type cells. In contrast, wild-type and MyD882/2
macrophages released similar amounts of AA in response to
particulate b-glucan. The upregulation of COX-2 6 hours after
adding C. albicans was almost completely ablated in MyD882/2
peritoneal macrophages, and the production of PGE2, PGI2,
and LTC4 at 6 hours was reduced by 80–90% (Suram et al.,
2006). These results suggest a major role for dectin-1 in the
early release of AA and of TLR2, the action of which depends
on the MyD88 adaptor, in the activation of kB-dependent
transcription and COX-2 expression in the late phase of
eicosanoid production (Fig. 1). The translation of this paradigm
to clinical settings is especially relevant to understand the
outcome of polymicrobial infections such as peritonitis, in
which Candida spp. accompanies either Gram-positive or
Gram-negative bacteria. Whereas monomicrobial infection is
nonlethal, coinfection with the same doses leads to a 40%
mortality rate and increases the microbial burden in the kidney and spleen. Notably, coinfection is associated with a
synergistic production of PGE2 and blockade of the COX routes
prevents mortality (Peters and Noverr, 2013). A sound
explanation for the molecular mechanism whereby PGE2 leads
to an immunocompromised state during Candida spp. infection
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colony-stimulating factor elicit profound changes on the
expression of receptors such as DC-SIGN and the dectin-1 B
isoform, that is, the isoform displaying the most efficient
productive binding to b-glucans (Rosas et al., 2008; Municio
et al., 2013). Macrophages cultured in the presence of human
serum show a high sensitivity to LPS as judged from a rapid
induction of COX-2 and a high production of PGE2. In contrast,
particulate zymosan, an extract of the Saccharomyces cerevisiae
cell wall mainly composed of b-glucans, only induces COX-2
expression several hours after particle uptake (Municio et al.,
2013). This putative phagolysosomal route of PGE2 production
is synergistically enhanced by low concentrations of LPS, which
agrees with the results observed with crystal-like materials
(Kuroda et al., 2011). These findings are relevant to vaccine
technology, since the release of PGE2 under these conditions
helps explain the adjuvant effect of alum, one of the few approved adjuvants for use in humans, and maybe of b-glucans as
well (Huang et al., 2010). The response of the macrophages is
also influenced by their origin. For instance, peritoneal macrophages readily respond to bacterial products, whereas this
response is less pronounced or even absent in bone marrow–
derived macrophages. From a pathophysiological point of
view, this is most evident in the response termed eicosanoid
storm observed in response to bacterial toxins, where systemic
inflammasome-dependent activation of cPLA2 and COX-1 in
peritoneal macrophages by intraperitoneal injection of flagellin
leads to a rapid loss of intravascular fluid, hemoconcentration,
hypothermia, and death, which is not observed in mice deficient
in COX-1 (von Moltke et al., 2012).
DCs. DCs are professional antigen-presenting cells that
bridge the innate and the adaptive immune response due to
their ability to stimulate naive T cells and initiate immune
responses through the activation of Th cells. PGE2 is a key
factor for the surface expression of CCR7 and the ensuing
acquisition of responsiveness to CCL21 and CCL19, which are
expressed in lymphatic vessels and the T cell areas of lymph
nodes (Scandella et al., 2002; Kabashima et al., 2003). Mice
lacking CCR7 fail to migrate into draining lymph nodes;
congruent with this pivotal function of PGE2, failure of DCs to
produce PGE2 has been considered a major obstacle for the
successful application of DCs in therapy (Thurnher et al.,
2001; Zelle-Rieser et al., 2002). Several reports have stressed
the following roles of 5-lipoxygenase products in DC function:
1) deficient extracellular export of LTC4 is associated with
a decreased migratory response of DCs (Robbiani et al., 2000),
2) cysteinyl-LT increase IL-10 production by myeloid DCs in
a murine model of murine asthma (Machida et al., 2004), and
3) the dectin-2/cysteinyl-LT pathway is critical for the
induction of Th2 immunity to major allergens (Barrett et al.,
2011). Similar to the distinct responses observed in the
different types of differentiated macrophages, AA metabolism
in DCs shows distinct patterns in mature and immature DCs.
Whereas the release of AA elicited by some ligands showed no
difference between immature and tumor necrosis factor-a
(TNFa)–mature cells, an enhanced expression of COX-2 was
best observed in immature DCs (Valera et al., 2008), thus
highlighting the distinct patterns of response associated with
environmental cues. In the case of LPS, DCs express the LPS
coreceptor CD14 at lower levels than macrophages (Segura
et al., 2013) and this may explain the different intensity of the
response. Regarding C-type lectin receptors, the engagement
of dectin-1 has been the object of close attention since it is
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AA Metabolites Are Major Modulators of the
Release of Cytokines from DCs
IL-10, PGE2, and Downregulation of the Inflammatory Response. The induction of cytokines by fungal PAMPs
has been the subject of detailed analysis. In the case of
b-glucans, the pattern of cytokines includes a high production
of TNFa, IL-6, IL-10, and IL-23, and a low secretion of IL-12
p70 (Rogers et al., 2005; Dillon et al., 2006; Gerosa et al.,
2008). Since these cytokines are produced concomitantly with
the release of eicosanoids, the question arises as to the role
played by eicosanoids in the induction of those cytokines. The
induction of the expression of TNFa and IL-6 can be explained
on the basis of the activation of NF-kB, but the expression of
IL-10 requires close attention due to its complex mechanism
of regulation and its role in the downregulation of the inflammatory response. Most recent views have focused on
signal transducer and activator of transcription 3 (Benkhart
et al., 2000; Chang et al., 2007; Weichhart et al., 2008;
Villagra et al., 2009) and CREB (Platzer et al., 1999; Hu et al.,
2006; Alvarez et al., 2009a). The central role of CRE-dependent
transcription on il10 regulation explains its strong PGE2
dependence, since one of the best effects of PGE2 is the activation of the system E prostanoid (EP) receptor/cAMP/PKA,
which phosphorylates S133-CREB and creates a docking site
for the coactivator CREB-binding protein and the initiation of
il10 transactivation. In addition, PKA activity inhibits saltinduced kinases (SIKs), the function of which is to allow the
cytoplasmic retention of CREB coactivators transducer of regulated CREB activity (TORC)/CREB-regulated transcriptional
coactivator (CRTC) 2 and TORC/CRTC3 through their cytoplasmic docking to 14-3-3 proteins. In keeping with this mechanism,
inhibition of SIK activity by the kinase inhibitor MRT67307 (N[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin4-yl]amino]propyl]cyclobutanecarboxamide) elevates IL-10
production by inducing the dephosphorylation of TORC/CRTC3,
its dissociation from 14-3-3 proteins, and its translocation to
the nucleus where it enhances the gene transcription program
controlled by CREB. Proof of concept of the involvement of
PGE2 in the PKA/SIK/CRTC3 pathway was recently provided
(Clark et al., 2012; Mackenzie et al., 2013a). Taken together,
these data show that PGE2 acting through EP receptors
modulates two upstream elements of the EP/PKA/SIK/CRTCCREB pathway that reprograms macrophages to an antiinflammatory phenotype (Fig. 2). A corollary to these findings
is that inhibition of SIK can be used as a molecular target to
switch macrophage into an anti-inflammatory phenotype. In
addition to the robust connection between PGE2 and IL-10 that
explains a portion of the anti-inflammatory phenotypes in
macrophages and DC, PGE2 can still repress TLR-induced
cytokine induction in the absence of IL-10 (van der Pouw Kraan
et al., 1995; Mackenzie et al., 2013a). Several studies have
disclosed the distinct mechanisms involved in the modulation
of cytokine production elicited by PGE2. Whereas the inhibitory
effect of PGE2 on IL-6 induction was dependent on IL-10 as
judged from its reversal by anti–IL-10 antibody, the production
of IL-12 p70 was not influenced by this treatment (van der
Pouw Kraan et al., 1995). The inhibitory effect on the induction
of TNFa has been explained through PKA-anchoring protein
95, which positions the kinase in close proximity to its substrates, and interference with the phosphorylation of Ser536 in
the C-terminal transactivation domain of the NF-kB family
protein p105 (Wall et al., 2009). The inhibition of the inflammatory chemokines CCL3 and CCL4 has been explained through
a signaling route involving EP/exchange protein activated by
cAMP (EPAC)/phosphatidylinositol 3-kinase/protein kinase
B/glycogen synthase kinase 3, which results in an increased
binding of the CCAAT displacement protein to the regulatory
regions of a variety of genes, where it behaves as a potent
transcriptional repressor (Jing et al., 2004). Another way of
cross-talk between IL-10 and PGE2 production has been
disclosed by showing the inhibitory effect of IL-10 on ptgs2
mRNA expression. This was observed in different systems
(Niiro et al., 1995; Berg et al., 2001; Shibata et al., 2005) and a
mechanistic explanation was provided in a recent study by
showing that IL-10 regulates ptgs2 mRNA via tristetraprolinedependent degradation (Mackenzie et al., 2013b).
PGE2 and the IL-12 p70/IL-23 Balance. Some studies
have shown the involvement of PGE2 in the production of Th1
responses (Nagamachi et al., 2007; Yao et al., 2009), but most
work has stressed its ability to suppress the differentiation of
functionally competent Th1-inducing DCs (Kali
nski et al.,
1997). The most accepted mechanism is that PGE2 weakens
the Th1 response by inhibiting the production of the Th1polarizing cytokine IL-12 p70, because the expression of the
IL-12 p40 chain is not accompanied by the parallel expression
of the IL-12 p35 chain, which is necessary to form the
bioactive IL-12 p70 heterodimer. This effect is so strong that
the combination of PGE2 with other stimuli such as LPS and
the CD40 ligand also results in failure to induce IL-12 p70
(Kali
nski et al., 2001). Most recent studies have identified the
DC resulting from PGE2 exposure as myeloid-derived suppressor cells (MDSCs) capable of suppressing cytotoxic T lymphocyte
responses (Obermajer et al., 2011).
IL-23 plays a central role in the expansion and maintenance
of the Th17 phenotype, which agrees with the enhancing
role of PGE2 on IL-23 production and Th17 polarization
(Khayrullina et al., 2008; Boniface et al., 2009). This effect
seems restricted to DCs and has not been observed in macrophages (Kalim and Groettrup, 2013). A recent study deciphered
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has been reported recently by showing that PGE2 promotes the
formation of a complex between the actin depolymerization
factor cofilin-1 and phosphatase and tensin homolog deleted on
chromosome 10 that decreases polymerization of F-actin and
increases monomeric G-actin (Serezani et al., 2012). A recent
study disclosed how the timing of eicosanoid production may be
coupled to either pro- and anti-inflammatory responses during
Candida infection (Suram et al., 2013). Granulocyte-colony
stimulating factor (csf3 gene), a cytokine that regulates the
production and function of polymorphonuclear leukocytes, was
the gene showing the highest degree of induction in response to
Candida and its expression was reduced in cPLA22/2 animals.
The expression of il10 increased 78-fold in cPLA2a1/1 mice
compared with only 7-fold in the cPLA22/2 mice. Conversely,
TNFa expression was increased in cPLA2a2/2 mice treated
with Candida compared with wild-type animals. These findings are in keeping with the reported role of PGE2 in the
induction of the Th17 response and the central role of IL-17 in
host defense in candidiasis (Conti et al., 2009; Ferwerda et al.,
2009; Puel et al., 2011), and also show that Candida stimulates
an autocrine loop in macrophages involving cPLA2a, PG, and
cAMP that globally effects expression of genes involved in host
defense and the control of inflammation.
Eicosanoids in Innate Immunity
193
the PGE2-triggered signaling pathway from the most proximal EP receptors to transcription factor activation and binding to the promoter of il23a (i.e., the gene encoding the IL-23
p19 chain that dimerizes with IL-12 p40 to form the IL-23
heterodimer) (Kocieda et al., 2012). This mechanism is consistent with the aforementioned general route including
EP receptors/cAMP/PKA/P-CREB, but a portion of the effect
depends on the activation of EPAC by cAMP and is related to
an effect on C/EBPb transcriptional activity rather than on
CREB-mediated trans-activation. The response is mediated
primarily through EP4 and to a lesser extent via EP2. The
effect of PGE2 was only observed when it was used in combination with LPS, which is consistent with the need for
cooperation with other transcription factors activated by LPS,
such as NF-kB and/or C/EBPb. Further analysis showed that
two putative CREB binding sites in the il23a promoter were
involved in transcriptional regulation and that the CREB
distal site is an important regulator of EP4-induced il23a
transcription (Fig. 3). A thorough scrutiny of the distinct role
of the different EP receptors in human DC was recently
reported (Poloso et al., 2013). By using selective EP receptor
antagonists, it was observed that PGE2 controls IL-23 release
in a dose-dependent manner by differential use of EP2 and
EP4. Low concentrations of PGE2 trans-activate il23a via
EP4, whereas concentrations above 50 nM suppress IL-23 by
an EP2-dependent mechanism.
The Contribution of Animal Models to Decipher
the Function of PGE2 in the Innate Immune
Response
The Different EP Receptor Subtypes. The apparently
opposing biologic effects of PGE2 can be explained by its
distinct actions on many cell types. On the one hand, PGE2
promotes local vasodilatation, inflammatory edema, and local
attraction and activation of leukocytes. On the other hand, its
prominent effects on the induction of suppressive IL-10 and
blunting of IL-12 p70 production account for its immunomodulatory properties. These actions explain that the most
outstanding effect of PGE2 in in vivo models is to keep
excessive inflammatory responses at bay. A risk derived from
this action is that it may contribute to the immune suppression
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Fig. 2. The mechanism whereby PGE2 promotes the transcription of il10 in LPS- and zymosan-stimulated macrophages and DCs. Binding of PGE2 to
the EP2 and EP4 receptors triggers the production of cAMP and the activation of PKA. PKA induces the phosphorylation of S133-CREB and the
phosphorylation/inactivation of SIKs. P-S133-CREB binds to the CRE site in the il10 promoter, whereas dephosphorylation of TORC/CRTC2 and TORC/
CRTC3 by the serine-threonine phosphatase calcineurin releases the cytoplasmic retention of these coactivators by binding to 14-3-3 proteins and allows
their nuclear translocation and interaction with the complex P-CREB/CREB-binding protein to initiate the transcriptional response. The scheme has
been elaborated from results reported by Alvarez et al. (2009a), Clark et al. (2012), and Mackenzie et al. (2013a). The indication of acetylated lysines is
explained by the relevance of these post-translational modifications related to the lysine acetyltransferase activity of CREB-binding protein.
194
Rodríguez et al.
associated with chronic inflammation and cancer. Notably,
PGE2 on its own induces high levels of COX-2 in differentiating
MDSCs and initiates a positive feedback loop that stabilizes
the suppressive functions of MDSCs (Obermajer et al., 2011).
The distinct effects of PGE2 are best explained not only by
the existence of four different EP receptors, but also by
the diversity resulting from multiple variants of EP3 due
to alternative splicing of its C-terminal tail. Although EP
receptors are G-protein coupled, they are structurally and
functionally distinct, have limited amino acid identity, and
show variable levels of expression among the different tissues.
EP3 and EP4 represent high-affinity receptors, whereas EP1
and EP2 require significantly higher concentrations of PGE2
for effective signaling (see Sugimoto and Narumiya, 2007, for
a review). EP2 and EP4 signaling mainly depends on the
cAMP/PKA/CREB pathway (Gas-coupling), and they mediate
the most relevant anti-inflammatory and suppressive activity of PGE2. However, a detailed scrutiny of the function of
EP2 and EP4 disclosed that EP4 ligation induces a weaker
stimulation of intracellular cAMP compared with the ligation
of EP2 expressed at similar levels. Unlike EP2, EP4 can also
be coupled to b-arrestin and b-catenin (Yokoyama et al.,
2013). This explains the formation of an EP4/b-arrestin 1/cSrc signaling complex that plays an important role in cancer
cell migration (Kim et al., 2010) and in DC function (De
Keijzer et al., 2013). EP1 is coupled to a yet unknown G
protein, but binding of PGE2 to this receptor type leads to
a transient increase in intracellular Ca21 concentration and
to activation of PLCb, presumably by coupling to a Gaq
protein. The G-protein coupling of EP3 is more promiscuous in
view of the different C-terminal splice variants that signal via
Gaq and Gai proteins and induce an increase of inositoltrisphosphate and Ca21 (Gaq-coupling) or a decrease of cAMP
(Gai-coupling). This array of differences in sensitivity, susceptibility to desensitization, and ability to activate different
signaling pathways among the different EP receptors allows
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Fig. 3. Cooperation of PGE2 and TLR4 signaling in the induction of il23a transcriptional activation in murine bone marrow–derived DCs. PGE2
activates transcription factors that cooperate with NF-kB proteins. Part of the signals are conveyed via cAMP and PKA and allow the activation of
CREB. In addition, EPAC contributes to the activation of C/EBPb that binds to a site in the proximal promoter. P, phosphate. This diagram was
constructed from data by Kocieda et al. (2012).
Eicosanoids in Innate Immunity
Concluding Remarks
Eicosanoids are generated as a result of the signaling
cascades triggered by the binding of PAMPs to their cognate
PRRs. This makes the innate immune response one of the
most relevant settings in which eicosanoids play a pathophysiological role. Signaling cascades based on phosphorylation
and Ca21-driven translocation of cPLA2a are involved in the
rapid generation of eicosanoids, whereas induction of the
expression of COX-2 by activation of transcription factors
such as NF-kB, CREB, and C/EBPb explains the delayed and
high-rate production of PGE2 and PGD2 associated with
processing the AA available as a result of the basal acylation/
deacylation cycle. The distinct ligand-binding properties of
the PRR, the different signaling mechanisms associated, and
the cooperation of receptors in the binding of microbialderived particles explain the different patterns of responses
that can be observed. Another layer of complexity is provided
by the role of opsonic proteins. In this connection, complement
coating of PAMPs seems essential for the activation of
polymorphonuclears and monocytes by particles mimicking
the fungal cell wall, whereas monocyte-derived DCs are a cell
type specially endowed to respond to fungal patterns in the
absence of opsonins. The analysis of PGE 2 effects has
disclosed its capacity for the following: 1) to inhibit phagocytosis and to enhance mortality in models of fungal and
polymicrobial infection, 2) to stabilize the suppressive functions of MDSCs, 3) to promote an anti-inflammatory phenotype in macrophages associated with a high production of
IL-10, and 4) to inhibit IL-12 p70 and to enhance the production of IL-23. The application of mechanistic data on the
role of kinases such as SYK and SIK in modulating PGE2
production and the selective modulation of EP receptor signaling can be valuable clues to develop useful pharmacological
tools to address infectious, autoimmune, and autoinflammatory
diseases.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Rodriguez,
Domingo, Municio, Alvarez, Hugo, Fernández, and Sánchez Crespo.
References
Alvarez Y, Municio C, Alonso S, Sánchez Crespo M, and Fernández N (2009a) The
induction of IL-10 by zymosan in dendritic cells depends on CREB activation by the
coactivators CREB-binding protein and TORC2 and autocrine PGE2. J Immunol
183:1471–1479.
Alvarez Y, Municio C, Alonso S, San Román JA, Sánchez Crespo M, and Fernández N
(2009b) Cyclooxygenase-2 induced by zymosan in human monocyte-derived dendritic cells shows high stability, and its expression is enhanced by atorvastatin. J
Pharmacol Exp Ther 329:987–994.
Aronoff DM, Canetti C, and Peters-Golden M (2004) Prostaglandin E2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated
increase in intracellular cyclic AMP. J Immunol 173:559–565.
Aronoff DM, Lewis C, Serezani CH, Eaton KA, Goel D, Phipps JC, Peters-Golden M,
and Mancuso P (2009) E-prostanoid 3 receptor deletion improves pulmonary host
defense and protects mice from death in severe Streptococcus pneumoniae infection. J Immunol 183:2642–2649.
Ballinger MN, Aronoff DM, McMillan TR, Cooke KR, Olkiewicz K, Toews GB, PetersGolden M, and Moore BB (2006) Critical role of prostaglandin E2 overproduction in
impaired pulmonary host response following bone marrow transplantation. J
Immunol 177:5499–5508.
Barrett NA, Rahman OM, Fernandez JM, Parsons MW, Xing W, Austen KF,
and Kanaoka Y (2011) Dectin-2 mediates Th2 immunity through the generation of
cysteinyl leukotrienes. J Exp Med 208:593–604.
Blander JM and Sander LE (2012) Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat Rev Immunol 12:215–225.
Benkhart EM, Siedlar M, Wedel A, Werner T, and Ziegler-Heitbrock HW (2000)
Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. J Immunol
165:1612–1617.
Berg DJ, Zhang J, Lauricella DM, and Moore SA (2001) Il-10 is a central regulator of
cyclooxygenase-2 expression and prostaglandin production. J Immunol 166:
2674–2680.
Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan
TK, McKenzie BS, Kastelein RA, Cua DJ, and de Waal Malefyt R (2009) Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP
and EP2/EP4 receptor signaling. J Exp Med 206:535–548.
Brogliato AR, Antunes CA, Carvalho RS, Monteiro AP, Tinoco RF, Bozza MT, Canetti
C, Peters-Golden M, Kunkel SL, and Vianna-Jorge R et al. (2012) Ketoprofen
impairs immunosuppression induced by severe sepsis and reveals an important
role for prostaglandin E2. Shock 38:620–629.
Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, and Gordon S
(2003) Dectin-1 mediates the biological effects of b-glucans. J Exp Med 197:
1119–1124.
Brown GD, Taylor PR, Reid DM, Willment JA, Williams DL, Martinez-Pomares L,
Wong SY, and Gordon S (2002) Dectin-1 is a major b-glucan receptor on macrophages. J Exp Med 196:407–412.
Buczynski MW, Stephens DL, Bowers-Gentry RC, Grkovich A, Deems RA,
and Dennis EA (2007) TLR-4 and sustained calcium agonists synergistically produce eicosanoids independent of protein synthesis in RAW264.7 cells. J Biol Chem
282:22834–22847.
Cambi A, Netea MG, Mora-Montes HM, Gow NA, Hato SV, Lowman DW, Kullberg
BJ, Torensma R, Williams DL, and Figdor CG (2008) Dendritic cell interaction
with Candida albicans critically depends on N-linked mannan. J Biol Chem 283:
20590–20599.
Casanova JL, Abel L, and Quintana-Murci L (2011) Human TLRs and IL-1Rs in host
defense: natural insights from evolutionary, epidemiological, and clinical genetics.
Annu Rev Immunol 29:447–491.
Chang EY, Guo B, Doyle SE, and Cheng G (2007) Cutting edge: involvement of the
type I IFN production and signaling pathway in lipopolysaccharide-induced IL-10
production. J Immunol 178:6705–6709.
Clark JD, Lin LL, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, Milona N,
and Knopf JL (1991) A novel arachidonic acid-selective cytosolic PLA2 contains
a Ca(21)-dependent translocation domain with homology to PKC and GAP. Cell 65:
1043–1051.
Clark K, MacKenzie KF, Petkevicius K, Kristariyanto Y, Zhang J, Choi HG, Peggie
M, Plater L, Pedrioli PG, and McIver E et al. (2012) Phosphorylation of CRTC3 by
the salt-inducible kinases controls the interconversion of classically activated and
regulatory macrophages. Proc Natl Acad Sci USA 109:16986–16991.
Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017
for adaptable patterns of responses at different stages of the
immune response.
Animal Studies as a Proof of Concept. Studies in
animal models of infection have shown that PGE2 differentially affects cytokine production depending on the developmental state of the cell. In contrast to in vitro studies in which
PGE2 was found to enhance the Th17 immune response
(Khayrullina et al., 2008), PGE2 has been reported to suppress antifungal immunity by inhibiting IFN regulatory
factor 4 function and IL-17 expression in T cells in a mouse
model of Cryptococcus neoformans infection (Valdez et al.,
2012). Likewise, EP2 and EP4 activation suppresses pulmonary host defenses through increases in cAMP (Aronoff et al.,
2004; Ballinger et al., 2006; Sadikot et al., 2007). EP3 is also
involved in the suppression of host defenses, since EP32/2 are
protected from pneumococcal mortality (Aronoff et al., 2009).
Studies addressing the role of PGE2 in the development of
immunosuppression secondary to sepsis in a model of cecal
ligation and puncture complemented with secondary infection
with Aspergillus fumigatus, disclosed that inhibition of COX
was associated with improved survival to secondary infection.
EP4 receptors were identified as the main type involved in
modulating cytokine production (Brogliato et al., 2012).
Altogether, these data indicate that the predominant function
of PGE2 in vivo consists of the downregulation of the phagocytic activity and the immune response. Consistent with PGE2
being the most abundant eicosanoid at sites of inflammation,
there is not a definite notion of the function of the distinct
LT during infections. However, the notion has emerged from
pharmacological and genetic models in mice deficient in
5-lipoxygenase that the cAMP-reducing action of LTB4 carried
out on the Gai-coupled, high-affinity LTB4 receptor 1 receptor
enhances microbial phagocytosis during Streptococcus pyogenes
infection and may exert a function opposed to that of PGE2
(Soares et al., 2013).
195
196
Rodríguez et al.
Kishor A, Tandukar B, Ly YV, Toth EA, Suarez Y, Brewer G, and Wilson GM
(2013) Hsp70 is a novel posttranscriptional regulator of gene expression that
binds and stabilizes selected mRNAs containing AU-rich elements. Mol Cell Biol
33:71–84.
Kocieda VP, Adhikary S, Emig F, Yen JH, Toscano MG, and Ganea D (2012) Prostaglandin E2-induced IL-23p19 subunit is regulated by cAMP-responsive elementbinding protein and C/AATT enhancer-binding protein b in bone marrow-derived
dendritic cells. J Biol Chem 287:36922–36935.
Kool M, Willart MA, van Nimwegen M, Bergen I, Pouliot P, Virchow JC, Rogers N,
Osorio F, Reis e Sousa C, and Hammad H et al. (2011) An unexpected role for uric
acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34:527–540.
Kramer RM, Roberts EF, Um SL, Börsch-Haubold AG, Watson SP, Fisher MJ,
and Jakubowski JA (1996) p38 mitogen-activated protein kinase phosphorylates
cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that
proline-directed phosphorylation is not required for mobilization of arachidonic
acid by cPLA2. J Biol Chem 271:27723–27729.
Kuroda E, Ishii KJ, Uematsu S, Ohata K, Coban C, Akira S, Aritake K, Urade Y,
and Morimoto Y (2011) Silica crystals and aluminum salts regulate the production
of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity 34:514–526.
LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV,
Schweighoffer E, Tybulewicz V, Brown GD, and Ruland J et al. (2007) Syk- and
CARD9-dependent coupling of innate immunity to the induction of T helper cells
that produce interleukin 17. Nat Immunol 8:630–638.
Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, and Davis RJ (1993) cPLA2 is
phosphorylated and activated by MAP kinase. Cell 72:269–278.
Machida I, Matsuse H, Kondo Y, Kawano T, Saeki S, Tomari S, Obase Y, Fukushima
C, and Kohno S (2004) Cysteinyl leukotrienes regulate dendritic cell functions in
a murine model of asthma. J Immunol 172:1833–1838.
MacKenzie KF, Clark K, Naqvi S, McGuire VA, Nöehren G, Kristariyanto Y, van den
Bosch MWM, Mudaliar M, McCarthy PC, and Pattison MJ et al. (2013a) PGE(2)
induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol 190:565–577.
MacKenzie KF, Van Den Bosch MWM, Naqvi S, Elcombe SE, McGuire VA, Reith AD,
Blackshear PJ, Dean JLE, and Arthur JS (2013b) MSK1 and MSK2 inhibit
lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop. Mol Cell Biol 33:1456–1467.
Martinez-Pomares L (2012) The mannose receptor. J Leukoc Biol 92:1177–1186.
Municio C, Alvarez Y, Montero O, Hugo E, Rodríguez M, Domingo E, Alonso S,
Fernández N, and Crespo MS (2013) The response of human macrophages to
b-glucans depends on the inflammatory milieu. PLoS ONE 8:e62016 10.1371/
journal.pone.0062016.
Nagamachi M, Sakata D, Kabashima K, Furuyashiki T, Murata T, Segi-Nishida E,
Soontrapa K, Matsuoka T, Miyachi Y, and Narumiya S (2007) Facilitation of Th1mediated immune response by prostaglandin E receptor EP1. J Exp Med 204:
2865–2874.
Ng G, Sharma K, Ward SM, Desrosiers MD, Stephens LA, Schoel WM, Li T, Lowell
CA, Ling CC, and Amrein MW et al. (2008) Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in
dendritic cells. Immunity 29:807–818.
Niiro H, Otsuka T, Tanabe T, Hara S, Kuga S, Nemoto Y, Tanaka Y, Nakashima H,
Kitajima S, and Abe M et al. (1995) Inhibition by interleukin-10 of inducible
cyclooxygenase expression in lipopolysaccharide-stimulated monocytes: its underlying mechanism in comparison with interleukin-4. Blood 85:3736–3745.
Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, and Kalinski P (2011) Positive feedback between PGE2 and COX2 redirects the differentiation of human
dendritic cells toward stable myeloid-derived suppressor cells. Blood 118:
5498–5505.
Parti RP, Loper R, Brown GD, Gordon S, Taylor PR, Bonventre JV, Murphy RC,
Williams DL, and Leslie CC (2010) Cytosolic phospholipase a2 activation by Candida albicans in alveolar macrophages: role of dectin-1. Am J Respir Cell Mol Biol
42:415–423.
Peters BM and Noverr MC (2013) Candida albicans-Staphylococcus aureus polymicrobial peritonitis modulates host innate immunity. Infect Immun 81:
2178–2189.
Platzer C, Fritsch E, Elsner T, Lehmann MH, Volk HD, and Prösch S (1999) Cyclic
adenosine monophosphate-responsive elements are involved in the transcriptional
activation of the human IL-10 gene in monocytic cells. Eur J Immunol 29:
3098–3104.
Poloso NJ, Urquhart P, Nicolaou A, Wang J, and Woodward DF (2013) PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending
on receptor usage (EP2/EP4). Mol Immunol 54:284–295.
Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L,
Chrabieh M, and Audry M et al. (2011) Chronic mucocutaneous candidiasis in
humans with inborn errors of interleukin-17 immunity. Science 332:65–68.
Robbiani DF, Finch RA, Jäger D, Muller WA, Sartorelli AC, and Randolph GJ (2000)
The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3b, ELC)dependent mobilization of dendritic cells to lymph nodes. Cell 103:757–768.
Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams
DL, Gordon S, Tybulewicz VL, and Brown GD et al. (2005) Syk-dependent cytokine
induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22:507–517.
Rosas M, Liddiard K, Kimberg M, Faro-Trindade I, McDonald JU, Williams DL,
Brown GD, and Taylor PR (2008) The induction of inflammation by dectin-1 in vivo
is dependent on myeloid cell programming and the progression of phagocytosis. J
Immunol 181:3549–3557.
Ryan EP, Malboeuf CM, Bernard M, Rose RC, and Phipps RP (2006) Cyclooxygenase2 inhibition attenuates antibody responses against human papillomavirus-like
particles. J Immunol 177:7811–7819.
Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017
Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH,
Yu JJ, and Jung JW et al. (2009) Th17 cells and IL-17 receptor signaling are
essential for mucosal host defense against oral candidiasis. J Exp Med 206:
299–311.
Davis BK, Wen H, and Ting JP (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 29:707–735.
De Keijzer S, Meddens MB, Torensma R, and Cambi A (2013) The Multiple Faces of
Prostaglandin E2 G-protein coupled receptor signaling during the dendritic cell life
cycle. Int J Mol Sci 14:6542–6555.
Dennis EA, Cao J, Hsu YH, Magrioti V, and Kokotos G (2011) Phospholipase A2
enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 111:6130–6185.
Dillon S, Agrawal S, Banerjee K, Letterio J, Denning TL, Oswald-Richter K,
Kasprowicz DJ, Kellar K, Pare J, and van Dyke T et al. (2006) Yeast zymosan,
a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and
immunological tolerance. J Clin Invest 116:916–928.
Dixon DA, Blanco FF, Bruno A, and Patrignani P (2013) Mechanistic aspects of COX2 expression in colorectal neoplasia. Recent Results Cancer Res 191:7–37.
Domínguez-Soto A, Sierra-Filardi E, Puig-Kröger A, Pérez-Maceda B, Gómez-Aguado
F, Corcuera MT, Sánchez-Mateos P, and Corbí AL (2011) Dendritic cell-specific
ICAM-3-grabbing nonintegrin expression on M2-polarized and tumor-associated
macrophages is macrophage-CSF dependent and enhanced by tumor-derived IL-6
and IL-10. J Immunol 186:2192–2200.
Esser J, Gehrmann U, Salvado MD, Wetterholm A, Haeggström JZ, Samuelsson B,
Gabrielsson S, Scheynius A, and Rådmark O (2011) Zymosan suppresses leukotriene C₄ synthase activity in differentiating monocytes: antagonism by aspirin and
protein kinase inhibitors. FASEB J 25:1417–1427.
Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H,
Elbers CC, Johnson MD, Cambi A, and Huysamen C et al. (2009) Human dectin-1
deficiency and mucocutaneous fungal infections. N Engl J Med 361:1760–1767.
Gantner BN, Simmons RM, Canavera SJ, Akira S, and Underhill DM (2003) Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2.
J Exp Med 197:1107–1117.
Geijtenbeek TB and Gringhuis SI (2009) Signalling through C-type lectin receptors:
shaping immune responses. Nat Rev Immunol 9:465–479.
Gerosa F, Baldani-Guerra B, Lyakh LA, Batoni G, Esin S, Winkler-Pickett RT,
Consolaro MR, De Marchi M, Giachino D, and Robbiano A et al. (2008) Differential
regulation of interleukin 12 and interleukin 23 production in human dendritic
cells. J Exp Med 205:1447–1461.
Girotti M, Evans JH, Burke D, and Leslie CC (2004) Cytosolic phospholipase A2
translocates to forming phagosomes during phagocytosis of zymosan in macrophages. J Biol Chem 279:19113–19121.
Goodridge HS, Reyes CN, Becker CA, Katsumoto TR, Ma J, Wolf AJ, Bose N,
Chan AS, Magee AS, and Danielson ME et al. (2011) Activation of the innate
immune receptor Dectin-1 upon formation of a ‘phagocytic synapse’. Nature 472:
471–475.
Goodridge HS, Shimada T, Wolf AJ, Hsu YM, Becker CA, Lin X, and Underhill DM
(2009) Differential use of CARD9 by dectin-1 in macrophages and dendritic cells. J
Immunol 182:1146–1154.
Hammarström S, Murphy RC, Samuelsson B, Clark DA, Mioskowski C, and Corey EJ
(1979) Structure of leukotriene C. Identification of the amino acid part. Biochem
Biophys Res Commun 91:1266–1272.
Hara H, Ishihara C, Takeuchi A, Imanishi T, Xue L, Morris SW, Inui M, Takai T,
Shibuya A, and Saijo S et al. (2007) The adaptor protein CARD9 is essential for the
activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat
Immunol 8:619–629.
Harizi H, Juzan M, Moreau JF, and Gualde N (2003) Prostaglandins inhibit 5lipoxygenase-activating protein expression and leukotriene B4 production from
dendritic cells via an IL-10-dependent mechanism. J Immunol 170:139–146.
Hu X, Paik PK, Chen J, Yarilina A, Kockeritz L, Lu TT, Woodgett JR, and Ivashkiv
LB (2006) IFN-g suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24:563–574.
Huang H, Ostroff GR, Lee CK, Specht CA, and Levitz SM (2010) Robust stimulation
of humoral and cellular immune responses following vaccination with antigenloaded b-glucan particles. MBio 1: e00164–e001610.
Janeway CA, Jr (1989) Approaching the asymptote? Evolution and revolution in
immunology. Cold Spring Harb Symp Quant Biol 54:1–13.
Jing H, Yen JH, and Ganea D (2004) A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2. J Biol Chem 279:55176–55186.
Kabashima K, Sakata D, Nagamachi M, Miyachi Y, Inaba K, and Narumiya S (2003)
Prostaglandin E2-EP4 signaling initiates skin immune responses by promoting
migration and maturation of Langerhans cells. Nat Med 9:744–749.
Kalim KW and Groettrup M (2013) Prostaglandin E2 inhibits IL-23 and IL-12 production by human monocytes through down-regulation of their common p40 subunit. Mol Immunol 53:274–282.
Kali
nski P, Hilkens CM, Snijders A, Snijdewint FG, and Kapsenberg ML (1997) IL12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote
type 2 cytokine production in maturing human naive T helper cells. J Immunol
159:28–35.
Kali
nski P, Vieira PL, Schuitemaker JH, de Jong EC, and Kapsenberg ML (2001)
Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer. Blood 97:3466–3469.
Kellaway CH and Trethewie ER (1940) The liberation of a slow-reacting smooth
muscle-stimulating substance in anaphylaxis. Q J Exp Physiol 30:121–145.
Khayrullina T, Yen JH, Jing H, and Ganea D (2008) In vitro differentiation of dendritic cells in the presence of prostaglandin E2 alters the IL-12/IL-23 balance and
promotes differentiation of Th17 cells. J Immunol 181:721–735.
Kim JI, Lakshmikanthan V, Frilot N, and Daaka Y (2010) Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. Mol
Cancer Res 8:569–577.
Eicosanoids in Innate Immunity
Thurnher M, Zelle-Rieser C, Ramoner R, Bartsch G, and Höltl L (2001) The disabled
dendritic cell. FASEB J 15:1054–1061.
van der Pouw Kraan TC, Boeije LC, Smeenk RJ, Wijdenes J, and Aarden LA (1995)
Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp
Med 181:775–779.
Valdez PA, Vithayathil PJ, Janelsins BM, Shaffer AL, Williamson PR, and Datta SK
(2012) Prostaglandin E2 suppresses antifungal immunity by inhibiting interferon
regulatory factor 4 function and interleukin-17 expression in T cells. Immunity 36:
668–679.
Valera I, Fernández N, Trinidad AG, Alonso S, Brown GD, Alonso A, and Crespo MS
(2008) Costimulation of dectin-1 and DC-SIGN triggers the arachidonic acid cascade in human monocyte-derived dendritic cells. J Immunol 180:5727–5736.
Villagra A, Cheng F, Wang H-W, Suarez I, Glozak M, Maurin M, Nguyen D, Wright KL,
Atadja PW, and Bhalla K et al. (2009) The histone deacetylase HDAC11 regulates the
expression of interleukin 10 and immune tolerance. Nat Immunol 10:92–100.
Vogt G and Nathan C (2011) In vitro differentiation of human macrophages with
enhanced antimycobacterial activity. J Clin Invest 121:3889–3901.
von Moltke J, Trinidad NJ, Moayeri M, Kintzer AF, Wang SB, van Rooijen N, Brown
CR, Krantz BA, Leppla SH, and Gronert K et al. (2012) Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490:107–111.
Wada M, Saunders TL, Morrow J, Milne GL, Walker KP, Dey SK, Brock TG, Opp
MR, Aronoff DM, and Smith WL (2009) Two pathways for cyclooxygenase-2 protein
degradation in vivo. J Biol Chem 284:30742–30753.
Wall EA, Zavzavadjian JR, Chang MS, Randhawa B, Zhu X, Hsueh RC, Liu J, Driver
A, Bao XR, and Sternweis PC et al. (2009) Suppression of LPS-induced TNF-a
production in macrophages by cAMP is mediated by PKA-AKAP95-p105. Sci Signal 2:ra28.
Weichhart T, Costantino G, Poglitsch M, Rosner M, Zeyda M, Stuhlmeier KM, Kolbe
T, Stulnig TM, Hörl WH, and Hengstschläger M et al. (2008) The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29:565–577.
Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, Sugimoto Y, and Narumiya
S (2009) Prostaglandin E2-EP4 signaling promotes immune inflammation through
Th1 cell differentiation and Th17 cell expansion. Nat Med 15:633–640.
Yokoyama U, Iwatsubo K, Umemura M, Fujita T, and Ishikawa Y (2013) The prostanoid EP4 receptor and its signaling pathway. Pharmacol Rev 65:1010–1052.
Zelle-Rieser C, Ramoner R, Artner-Dworzak E, Casari A, Bartsch G, and Thurnher M
(2002) Human monocyte-derived dendritic cells are deficient in prostaglandin E2
production. FEBS Lett 511:123–126.
Address correspondence to: Dr. Mariano Sánchez Crespo, Institute of
Biology and Molecular Genetics, Spanish National Research Council, C/Sanz y
Forés s/n, 47003 Valladolid, Spain. E-mail: [email protected]
Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017
Sadikot RT, Zeng H, Azim AC, Joo M, Dey SK, Breyer RM, Peebles RS, Blackwell TS,
and Christman JW (2007) Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX-2. Eur J Immunol 37:1001–1009.
Scandella E, Men Y, Gillessen S, Förster R, and Groettrup M (2002) Prostaglandin E2
is a key factor for CCR7 surface expression and migration of monocyte-derived
dendritic cells. Blood 100:1354–1361.
Sato K, Yang XL, Yudate T, Chung JS, Wu J, Luby-Phelps K, Kimberly RP, Underhill
D, Cruz PD, Jr, and Ariizumi K (2006) Dectin-2 is a pattern recognition receptor for
fungi that couples with the Fc receptor g chain to induce innate immune responses.
J Biol Chem 281:38854–38866.
Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, Dalod M,
Soumelis V, and Amigorena S (2013) Human inflammatory dendritic cells induce
Th17 cell differentiation. Immunity 38:336–348.
Serezani CH, Kane S, Medeiros AI, Cornett AM, Kim SH, Marques MM, Lee SP,
Lewis C, Bourdonay E, and Ballinger MN et al. (2012) PTEN directly activates the
actin depolymerization factor cofilin-1 during PGE2-mediated inhibition of
phagocytosis of fungi. Sci Signal 5:ra12.
Shibata Y, Nishiyama A, Ohata H, Gabbard J, Myrvik QN, and Henriksen RA (2005)
Differential effects of IL-10 on prostaglandin H synthase-2 expression and prostaglandin E2 biosynthesis between spleen and bone marrow macrophages. J Leukoc Biol 77:544–551.
Shio MT, Eisenbarth SC, Savaria M, Vinet AF, Bellemare MJ, Harder KW, Sutterwala
FS, Bohle DS, Descoteaux A, and Flavell RA et al. (2009) Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog 5:
e1000559.
Sica A and Mantovani A (2012) Macrophage plasticity and polarization: in vivo
veritas. J Clin Invest 122:787–795.
Soares EM, Mason KL, Rogers LM, Serezani CH, Faccioli LH, and Aronoff DM (2013)
Leukotriene B4 enhances innate immune defense against the puerperal sepsis
agent Streptococcus pyogenes. J Immunol 190:1614–1622.
Sugimoto Y and Narumiya S (2007) Prostaglandin E receptors. J Biol Chem 282:
11613–11617.
Suram S, Brown GD, Ghosh M, Gordon S, Loper R, Taylor PR, Akira S, Uematsu S,
Williams DL, and Leslie CC (2006) Regulation of cytosolic phospholipase A2 activation and cyclooxygenase 2 expression in macrophages by the b-glucan receptor. J
Biol Chem 281:5506–5514.
Suram S, Gangelhoff TA, Taylor PR, Rosas M, Brown GD, Bonventre JV, Akira S,
Uematsu S, Williams DL, and Murphy RC et al. (2010) Pathways regulating cytosolic phospholipase A2 activation and eicosanoid production in macrophages by
Candida albicans. J Biol Chem 285:30676–30685.
Suram S, Silveira LJ, Mahaffey S, Brown GD, Bonventre JV, Williams DL, Gow
NAR, Bratton DL, Murphy RC, and Leslie CC (2013) Cytosolic phospholipase A(2)a
and eicosanoids regulate expression of genes in macrophages involved in host defense and inflammation. PLoS ONE 8:e69002.
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