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144
Review
TRENDS in Immunology Vol.23 No.3 March 2002
Prostaglandins as modulators of
immunity
Sarah G. Harris, Josue Padilla, Laura Koumas, Denise Ray and Richard P. Phipps
Prostaglandins are potent lipid molecules that affect key aspects of immunity.
The original view of prostaglandins was that they were simply
immunoinhibitory. This review focuses on recent findings concerning
∆12,14-PGJ2, and
prostaglandin E2 (PGE2) and the PGD2 metabolite 15-deoxy-∆
their divergent roles in immune regulation. We will highlight how these two
seminal prostaglandins regulate immunity and inflammation, and play an
emerging role in cancer progression. Understanding the diverse activities of
these prostaglandins is crucial for the development of new therapies aimed at
immune modulation.
Interest in the ability of prostaglandin E2 (PGE2) to
regulate the immune system has exploded in the past
decade. Many new and exciting data have emerged
concerning the role of PGE2 in cells of the immune
system and disease states. In this review, we will
provide highlights of that research, focusing first on
the interactions of PGE2 with T cells, B cells and
antigen-presenting cells (APCs). Second, the role of
PGE2 in two disease states that have strong immune
components – periodontal disease and cancer – will be
discussed. Finally, we will summarize the effects of a
newly discovered and prominent prostaglandin,
15-deoxy-∆12,14-PGJ2 (herein referred to as
15-d-PGJ2), on the immune system. The volume of
literature describing the roles of this lipid has
increased exponentially in recent years. We will
review the actions of 15-d-PGJ2 on cells and
specifically, its effects on inflammation and cancer.
Prostaglandins
Sarah G. Harris
Josue Padilla
Laura Koumas
Denise Ray
Depts of Microbiology
and Immunology and the
James P. Wilmot Cancer
Center,
Richard P. Phipps*
Depts of Microbiology
and Immunology,
Environmental Medicine,
Pediatrics, and Obstetrics
and Gynecology, and the
James P. Wilmot Cancer
Center, University of
Rochester School of
Medicine and Dentistry,
601 Elmwood Avenue,
Rochester, NY 14642,
USA.
*e-mail: Richard_Phipps@
urmc.rochester.edu
Prostaglandins are small lipid molecules that
regulate numerous processes in the body, including
kidney function, platelet aggregation,
neurotransmitter release and modulation of immune
function [1,2]. The production of prostaglandins
begins with the liberation of arachidonic acid from
membrane phospholipids by phospholipase A2 in
response to inflammatory stimuli. Arachidonic acid is
converted to PGH2 by the cyclooxygenase enzymes
COX-1 and COX-2 (known formally as prostaglandin
endoperoxide H synthases). Generally, it is thought
that COX-1 is expressed constitutively in most tissues
of the body and acts to maintain homeostatic
processes, such as mucus secretion. COX-2, by
contrast, is mainly an inducible enzyme and is
involved primarily in the regulation of inflammation
[3]. The recent development of COX-1- and COX-2knockout mice has provided much information
concerning the roles of these enzymes in
development, inflammation and carcinogenesis [4,5].
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Membrane phospholipids
Phospholipase A2
Arachidonic acid
COX-1
LPS
IL-1
TNF-α
+
COX-2
Prostaglandin H2
Prostaglandin synthases
PGF2α
PGI2
PGD2
O
COOH
COOH
OH
OH
PGE2
O
15-d-PGJ2
TRENDS in Immunology
Fig. 1. Pathway of prostaglandin production. Arachidonic acid is
liberated from membranes by phospholipase A2. The cyclooxygenase
enzymes (COX-1 and COX-2) produce prostaglandin H2 (PGH2) from
arachidonic acid. PGH2 is acted upon by prostaglandin synthases to
produce PGI2, PGD2, PGE2 and PGF2α. PGD2 is metabolized to
15-deoxy-∆12,14-PGJ2 (15-d-PGJ2). Abbreviations: IL-1, interleukin-1;
LPS, lipopolysaccharide; TNF-α, tumor necrosis factor α.
Cell-specific prostaglandin synthases convert PGH2
into a series of prostaglandins, including PGI2, PGF2α,
PGD2 and PGE2 (Fig. 1). The recent discovery that the
expression of PGE synthases can be induced by
proinflammatory stimuli provides another layer of
regulation and complexity in the production of
prostaglandins [6]. Upon production, prostaglandins
are released rapidly from cells and act near their site
of production by binding to specific, high-affinity
receptors on plasma membranes [7].
PGE2
One of the best known and most well-studied
prostaglandins is PGE2. PGE2 is produced by many
cells of the body – including fibroblasts, macrophages
and some types of malignant cells – and exerts its
actions by binding to one (or a combination) of its four
subtypes of receptor (EP1, EP2, EP3 and EP4). In the
mouse, the EP3 subtype consists of three different
isoforms, termed α, β and γ, and there are seven EP3
splice variants in humans identified to date. The
receptors are rhodopsin-type receptors containing
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Review
EP1
Gq/p
PLC
TRENDS in Immunology Vol.23 No.3 March 2002
EP2
EP4
EP3α, β and γ
Gs
Gs
Gi
AC
AC
PIP2
DAG
PKC
IP3
Ca2+
ATP
cAMP
Ca2+
PKA
cAMP
Gene regulation
TRENDS in Immunology
Fig. 2. Prostaglandin E2 receptor (EP-R) signaling pathways. EP-Rs are rhodopsin-type receptors with
seven transmembrane-spanning domains. The four main subtypes of EP-R (EP1–EP4) are coupled to
different G proteins and use different second messenger signaling pathways. EP1 is coupled to Gq/p
and ligand binding results in an increase in the level of intracellular calcium. EP2 and EP4 are coupled
to Gs proteins and induce the expression of cAMP, which leads to gene regulation. The three isoforms
of EP3 (α, β and γ) are coupled primarily to Gi and are most often inhibitory to cAMP. (There is some
evidence that additional signaling cascades might be activated by EP3 binding.) Abbreviations: AC,
adenylate cyclase; DAG, diacylglycerol; IP3, inositol triphosphate; PIP2, phosphatidylinositol
diphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.
seven hydrophobic transmembrane domains, coupled
through their intracellular sequences to specific
G proteins with different second messenger signaling
pathways [8] (Fig. 2). The regulation of expression of
the various subtypes of EP receptors on cells by
inflammatory agents, or even PGE2 itself, enables
PGE2 to affect tissues in a very specific manner [7,9].
Although knockout mice for all four EP receptors have
been produced, no functional analysis of the effects on
lymphocytes has been performed [10]. Recently,
several reports have documented the expression of
functional EP receptors (EP1, EP3 and EP4) on the
nuclear membranes of cells [11]. For example, EP3γ
and EP4 have been localized to the nuclear envelope of
endothelial cells. The receptors are functional,
because they can modulate transcription, including
that of the gene encoding inducible nitric oxide
synthase (iNOS) [11]. The discovery of nuclear EP
receptors provides an additional level to the
PGE2-mediated regulation of cells, and further study
is necessary to determine the processes that govern
the expression and function of the nuclear-localized
receptors.
T cells
PGE2 has diverse effects on the regulation and
activity of T cells. The majority of research on T cells
has focused on CD4+ cells, for which work has
concentrated on the roles of PGE2 in the modulation
of proliferation, apoptosis and cytokine production.
The inhibition of T-cell proliferation by PGE2 is well
established and currently, there is intense study to
determine the mechanism of inhibition. Ruggeri et al.
[12] showed that the inhibition of proliferation is
owing, in part, to the inhibition of polyamine
synthesis (i.e. spermine). PGE2 has been found also to
inhibit intracellular calcium release [13] and the
activity of p59 (fyn) protein tyrosine kinase [14]; both
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145
of these effects could be responsible for the observed
decrease in proliferation. Interestingly, EP receptors
have been implicated also in the inhibition of
proliferation owing to a decrease in the secretion of
interleukin-2 (IL-2). During mucosal inflammation,
for example, mucosal T cells up-regulate their
expression of certain EP receptors (e.g. EP4), and
there is a resulting decrease in the T-cell production
of IL-2 [15]. Therefore, although much research has
been carried out to account potentially for the
decrease in proliferation of T cells caused by PGE2,
further examination to find a definitive mechanism is
warranted.
The effects of PGE2 on the apoptosis of T cells are
dependent on the maturation and activation state of
the cell. PGE2 induces CD4+CD8+ double-positive
thymocytes to undergo apoptosis both in vitro and
in vivo [16]. In resting mature T cells, PGE2 induces
apoptosis also, which is associated with an increase in
the expression of c-Myc [17]. By contrast, PGE2
protects T cells from T-cell receptor (TCR)-mediated
activation-induced cell death by modulating the
expression of Fas ligand (FasL) on the T-cell surface.
PGE2 decreases FasL mRNA and protein expression,
which inhibits apoptosis [18]. Therefore, the induction
of apoptosis by PGE2 is involved in the selection of
immature thymocytes, thus shaping the T-cell
repertoire. In addition, PGE2 regulates differentially
the activities of mature resting and activated T cells
by inducing and inhibiting apoptosis, respectively.
PGE2 has a profound effect on the production of
cytokines by T cells. Recently, PGE2 has been
implicated in the enhancement of T helper 2
(Th2)-type responses. For example, PGE2 has no
effect on or enhances the production of Th2 cytokines,
such as IL-4, IL-5 and IL-10, by Th2 cells, but inhibits
drastically the production of Th1 cytokines, such as
interferon γ (IFN-γ) and IL-2, by Th1 cells [19] (Fig. 3).
The induction of the Th2 response by PGE2 is
mediated most probably by cAMP, because elements
that increase the level of cAMP mimic the effects of
PGE2 [2]. Although a few reports suggest that PGE2
inhibits Th2 responses [20], the vast majority of
reports shows that primarily, PGE2 has a
Th2-inducing activity on T cells. Harnessing the
ability of PGE2 to modulate Th responses and thus,
immunity in general could be extremely beneficial for
treating the numerous disorders in which there is a
dysregulated Th response.
Although less is known about the effects of PGE2
on CD8+ T cells, it has been shown that, as for CD4+
T cells, PGE2 can inhibit CD8+ T-cell proliferation
[21]. In terms of regulating cytokine production, PGE2
decreases the production of IFN-γ by CD8+ T-cell
clones through a cAMP-dependent pathway [22].
Such inhibition of IFN-γ production is consistent with
the dogma that PGE2 favors type-2 responses in
general. Therefore, PGE2 plays a variety of crucial
roles throughout the life of T cells, from the regulation
of positive and negative selection in the thymus to the
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146
TRENDS in Immunology Vol.23 No.3 March 2002
Antigen-presenting cells
PGE2
DC
T cell
Mφ
IL-4, IL-5, IL-10
IL-2, IFN-γ
TNF-α, IL-1β, IL-12, IL-12R
B cell
IL-10
IL-12
IgG1, IgE
TRENDS in Immunology
Fig. 3. Prostaglandin E2
(PGE2) enhances the
production of type-2
cytokines and antibodies.
PGE2 acts on T cells to
enhance their production
of interleukin-4 (IL-4), IL-5
and IL-10, but inhibits
their production of IL-2
and interferon γ (IFN-γ).
Acting on B cells, PGE2
stimulates isotype-class
switching to induce the
production of IgG1 and
IgE. PGE2 acts on antigenpresenting cells, such as
macrophages (Mφs) and
dendritic cells (DCs), to
induce the expression of
IL-10 and inhibit
expression of IL-12, IL-12
receptor (IL-12R), tumor
necrosis factor α (TNF-α)
and IL-1β. The overall
result is an enhancement
of T helper 2 (Th2)
responses and inhibition
of Th1 responses by PGE2.
regulation of proliferation, apoptosis and cytokine
production of mature cells.
B cells
PGE2 plays an important role in the development and
activity of B cells. In contrast to its effects on mature
B cells, PGE2 acts in an inhibitory manner on
immature and developing B cells. For example, PGE2
suppresses the proliferation of immature B cells, but
has no effect on, or even sometimes enhances, the
proliferation of mature B cells [23]. Also, PGE2 is a
potent inducer of immature B-cell apoptosis, but does
not induce cell death in mature B cells [24]. In addition,
B cells isolated from neonatal mice are susceptible to
PGE2-induced apoptosis, whereas B cells from mature
mice are unaffected [24]. Further evidence from the
studies of Shimozato and Kincade [25] confirms the
inhibitory role of PGE2 in B-cell development; mice
treated with PGE2 have fewer B-lineage precursors in
their bone marrow (BM) than untreated mice, which
implicates PGE2 as a regulator of the elimination of
self-reactive or defective B-cell precursors.
PGE2 regulates the activity of mature B cells by
inhibiting certain activation events but enhancing
Ig-class switching. Treatment of lipopolysaccharide
(LPS)- and IL-4-activated B cells with PGE2 inhibits
cell enlargement, MHC class II hyperexpression and
expression of FcεRII, the low-affinity receptor for IgE
[26]. As well as inhibiting the activation of B cells,
PGE2 stimulates the production of IgG1 and IgE (at the
expense of IgG3 and IgM) in LPS- and IL-4-stimulated
B cells by a cAMP-dependent mechanism [26]. This
induction of expression of IgE and IgG1 by PGE2 again
supports the theory that PGE2 acts predominantly to
induce Th2 responses (Fig. 3). Although not yet shown
directly, this implies a role for PGE2 in enhancing the
development of allergy and asthma. In addition to
being responsive to PGE2, an unusual B-lineage cell,
called the B/macrophage, expresses the cyclooxygenase
enzymes and can produce PGE2 upon stimulation [27].
The PGE2 produced by the B/macrophage can act on
other immune cells (such as T cells) to further induce
type-2 immune responses. Therefore, B-lineage cells
modulate immune responses by both producing and
responding to PGE2.
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APCs play a key role in B- and T-cell-mediated
immune responses. PGE2 modulates the activities of
‘professional’APCs, such as dendritic cells (DCs) and
macrophages, in a variety of ways. Immature DCs
take up antigen in peripheral tissues, which induces
their activation and subsequent migration to
lymphoid organs. In the lymph nodes, DCs mature
into cells able to present antigen to and prime T cells.
PGE2 has been suggested to play a key role in these
events. PGE2 has both stimulatory and inhibitory
effects on the activation of DCs, depending on the site
of encounter. In peripheral tissues, PGE2 seems to
have a stimulatory effect on DCs, inducing their
activation. Once the cells have migrated to lymphoid
organs, PGE2 assumes an inhibitory role, inhibiting
the maturation of DCs and their ability to present
antigen [28]. Also, PGE2 regulates the production of
cytokines by DCs, thus shaping the subsequent
immune response. For example, if PGE2 is present
during the priming of DCs with antigen, the DCs are
inhibited completely in their ability to produce IL-12.
These PGE2-primed DCs produce high levels of IL-10
[29]. The PGE2-primed DCs induce the differentiation
of naive T cells into Th2 cells directly – the T cells
produce high levels of IL-4 and no IFN-γ. This further
supports the role of PGE2 in biasing the immune
system towards Th2 and away from Th1 responses.
Furthermore, BM-derived DCs can produce PGE2
themselves [28] and thus, autoregulate their
functions in the immune system.
Another established function of PGE2 is the
regulation of cytokine production by activated
macrophages. The effects of PGE2 on macrophages
are suppressive for type-1 immune responses. PGE2
down-regulates the expression of the IL-12 receptor
and inhibits the production of tumor necrosis
factor α (TNF-α), IL-1β, IL-8 and IL-12 by
macrophages [30]. Similarly, PGE2 reduces the
production of TNF-α by LPS-treated peritoneal
macrophages [31]. Studies of zymosan-treated
mouse peritoneal macrophages show that PGE2
causes a down-regulation of TNF-α production and
an up-regulation of IL-10 production, through the
EP2 and EP4 receptors [32]. Therefore, PGE2 acts to
up-regulate type-2 responses in macrophages
(Fig. 3). As for some DCs, PGE2 is produced in large
quantities by macrophages, primarily in response to
proinflammatory mediators, such as IL-1 and LPS
[33]. Therefore, PGE2 might act as an autocrine
feedback regulator, because it has been shown to
positively regulate its own expression by
up-regulating the expression of COX-2.
PGE2 in disease
PGE2 plays an integral role in a myriad of infections
and diseases. We have chosen to highlight two
diseases for which PGE2 has been shown to be central
to disease progression – periodontal disease and
certain cancers.
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TRENDS in Immunology Vol.23 No.3 March 2002
147
concomitant reduction of periodontal disease
progression (Fig. 4).
MΦ
Alveolar bone
resorption
LPS
Bacterial
products
TNF-α
IL-1
COX-2
MMPs
Extracellular
matrix
destruction
PGE2
MMPs
Healthy
periodontium
Fibroblast
Tooth loss
Periodontitis
TRENDS in Immunology
Fig. 4. Prostaglandin E2 (PGE2) is a biochemical marker for and key element in the pathogenesis of
periodontal disease. Lipopolysaccharide (LPS) from periodontopathogenic bacteria elicits a complex
bacteria–host interaction. Infiltrating white blood cells, such as monocytes and/or macrophages,
release proinflammatory cytokines [e.g. interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)].
Levels of cyclooxygenase-2 (COX-2) are up-regulated, leading to high levels of PGE2. PGE2 induces
increases in vasopermeability and vasodilation, leading to redness and edema. PGE2 is also a potent
inducer of the production of matrix metalloproteinases (MMPs) by infiltrating and resident cells
(i.e. gingival and periodontal ligament fibroblasts). These bacteria–host interactions lead to the
degradation of connective tissue, alveolar bone destruction and eventually, tooth loss. Eliminating
PGE2 with cyclooxygenase inhibitors modulates the host’s overt response to the bacteria, thus
reducing periodontal disease progression.
Periodontal disease
Periodontitis is a chronic inflammatory process that
degrades the tooth support structures (i.e. gingiva,
periodontal ligament, cementum and alveolar bone).
Periodontal disease is thought to be induced by the
accumulation of bacterial plaque at the gum line. The
presence of bacterial plaque in the gingival crevice
elicits a complex bacteria–host interaction, which
leads to the degradation of connective tissue, alveolar
bone destruction and eventually, tooth loss. The host
responds to bacterial endotoxins (e.g. LPS) by
stimulating cells present in the periodontal tissues to
release proinflammatory mediators, such as IL-1β,
TNF-α and PGE2 (Fig. 4). It is the local action of
prostaglandins and cytokines, which play crucial
roles in the inflammatory process, that leads to the
pathology associated with periodontal disease.
Since the early 1970s, PGE2 has been used as a
biochemical marker for periodontitis, because
inflamed periodontal tissues have high levels of PGE2
[34]. PGE2 causes increased vasopermeability and
vasodilation, leading to redness and edema. Also,
PGE2 induces the synthesis of matrix
metalloproteinases (MMPs) by infiltrating and
resident cells, such as monocytes and fibroblasts,
respectively. MMPs cause connective-tissue
degradation and osteoclastic bone destruction, both of
which are hallmarks of periodontal disease [35].
Owing to the high-level expression of PGE2 and its
detrimental effects in the periodontium, there are
numerous models of periodontal disease in animals
and humans evaluating the effectiveness of
cyclooxygenase inhibitors. The suppression of PGE2
synthesis by these drugs diminishes greatly the loss
of periodontal connective tissue [34,36]. Thus, these
data indicate not only an association between disease
activity and levels of PGE2 within tissues, but that
eliminating PGE2 with cyclooxygenase inhibitors
(e.g. the COX-2-selective inhibitor Vioxx) leads to a
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Cancer
The relationship between enhanced cyclooxygenase
expression and selected cancers is becoming well
established (for review, see Ref. [37]). Over-expression
of COX-2 has been noted in many cancers, including,
but not limited to, cancers of the breast, colon and
prostate [37]. The discovery that the inhibition of
COX activity inhibits cancerous tumor growth in
many systems has further solidified our knowledge of
the integral role that cyclooxygenases play in tumor
progression. Key epidemiological studies reveal that
inhibiting the cyclooxygenase enzymes reduces the
incidence of certain cancers. For example, individuals
taking cyclooxygenase inhibitors have a 40–50%
reduction in the incidence of colorectal cancer [37].
Because the COX enzymes produce prostaglandins,
the roles that these mediators play in tumorigenesis
is under intense investigation also.
PGE2, which promotes tumor-cell survival, has
been found at higher concentrations in tumor tissues
than normal tissues [38]. PGE2 mediates tumor
survival by several mechanisms. It inhibits tumorcell apoptosis and induces tumor-cell proliferation
[39]. Also, PGE2 increases tumor progression by
altering cell morphology, and increasing cell motility
and migration [40]. In addition to the direct effects of
PGE2 on tumor cells, this lipid mediator induces the
production of metastasis-promoting MMPs and
stimulates angiogenesis [40] (Fig. 5). PGE2 acts also
as an immunomodulator (as described earlier), to
promote humoral and Th2-type immune responses
that do not favor tumor destruction, and inhibit
Th1-type responses that do favor tumor destruction.
Therefore, the relationship between PGE2 and tumor
progression is quite important, and further study in
the field is warranted to understand the additional
roles of this lipid. In the future, specific inhibition of
PGE2 by the inhibition of PGE synthases, for
example, might prove extremely beneficial for the
abrogation of tumor progression.
∆12,14-PGJ2
15-deoxy-∆
The J series of prostaglandins, once thought to
comprise inactive degradation products of PGD2, is
now well established as regulating diverse processes,
such as adipogenesis, inflammation and
tumorigenesis. 15-d-PGJ2 is the end-product
metabolite of PGD2 and is produced by a variety of
cells, including mast cells, T cells, platelets and
alveolar macrophages. The exact mechanism of entry
of 15-d-PGJ2 into cells is unknown, but it is possible
that 15-d-PGJ2 enters by an active transport system
similar to those described by Narumiya’s group for
other cyclopentanone prostaglandins (e.g. ∆-12 PGJ2)
[41]. Once inside the cell, an additional cryptic
mechanism allows transport of the cyclopentanone
prostaglandins into the nucleus, where they affect
Review
148
TRENDS in Immunology Vol.23 No.3 March 2002
PGD2
Cyclooxygenases
Key:
PGD2
PGE2
MMP
Apoptotic bleb
15-d-PGJ2
15-d-PGJ2
receptor?
Tumor cell
Active
transport
system
15-d-PGJ2
Anionic
carrier
protein
Cytoplasm
15-d-PGJ2
Nuclear
transporter
Apoptosis
Apoptosis
MMPs
Proliferation
Tumor promotion
MMPs
15-d-PGJ2
Binds to PPAR-γ
and regulates
transcription
Tumor inhibition
gene transcription (Fig. 6). Although it has never been
shown directly that 15-d-PGJ2 uses these
transporters, its similar structure to the other
prostaglandins makes this mechanism feasible. It is
possible also that locally produced PGD2 could enter a
cell by an anionic transporter molecule and then be
degraded to 15-d-PGJ2 once inside the cytoplasm [42].
These mechanisms are not, of course, mutually
exclusive. Once inside the cell, 15-d-PGJ2 was
thought traditionally to exert its effects by binding to
the peroxisome proliferator-activated receptor γ
(PPAR-γ) [43]. PPARs are a family of ligand-activated
nuclear transcription factors, which, upon the binding
of ligand, form a heterodimer with the retinoic
X receptor. This complex then binds to PPARresponsive elements (PPREs) in the promoter regions
of target genes [43]. PPAR-γ was found initially in
adipose tissue, where it plays a key role in the
regulation of adipogenesis. More recently, the
receptor has been found also in many immune cells,
including neutrophils, macrophages, T cells and
B cells [44].
There has been recent controversy over the link
between the action of 15-d-PGJ2 and PPAR-γ binding.
Initial reports focused on the ability of 15-d-PGJ2 to
bind to and activate PPAR-γ. For example, 15-d-PGJ2
inhibits T-cell proliferation and induces apoptosis of
T cells by a PPAR-γ-dependent mechanism [45,46].
More recently, however, evidence has shown that
there are also effects of 15-d-PGJ2 that are
independent of PPAR-γ activation (Fig. 6). For
example, 15-d-PGJ2 can down-regulate the production
of iNOS by microglial cells through PPAR-γindependent mechanisms [47]. Vaidya and colleagues
have shown that 15-d-PGJ2 can inhibit the production
of oxygen free radicals by neutrophils in a PPAR-γindependent manner [48]. Additionally, the inhibition
of IκB kinase can occur through PPAR-γ-independent
means [49]. Although the exact mechanism of
15-d-PGJ2 action in these systems is unknown, it has
been postulated that 15-d-PGJ2 could be acting
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Nucleus
Other mechanisms
to regulate
transcription
Proliferation
TRENDS in Immunology
Fig. 5. Opposing effects
of prostaglandin E2 (PGE2)
and 15-deoxy-∆12,14-PGJ2
(15-d-PGJ2) on tumor
cells. PGE2 and 15-d-PGJ2
have opposite effects on
malignant-cell
development. PGE2
promotes some types of
cancers by inducing the
production of matrix
metalloproteinases
(MMPs), leading to
enhanced metastasis.
PGE2 also induces cancercell proliferation and
inhibits apoptosis. By
contrast, 15-d-PGJ2
inhibits tumor formation.
15-d-PGJ2 decreases
MMP production, inhibits
malignant-cell
proliferation and
stimulates apoptosis.
PGD2
TRENDS in Immunology
Fig. 6. Possible modes of action of 15-deoxy-∆12,14-PGJ2 (15-d-PGJ2) in
the cell. Prostaglandin D2 (PGD2) is broken down into 15-d-PGJ2.
15-d-PGJ2 could gain entry to the cell by an active transport system, and
then enter the nucleus by a nuclear transporter, as described for other
cyclopentanone prostaglandins. Also, 15-d-PGJ2 could bind to an
undiscovered cytoplasmic receptor. Alternatively, PGD2 could gain
entry into the cell by means of an anionic carrier protein, and then be
metabolized in the cytoplasm to 15-d-PGJ2. 15-d-PGJ2 could then gain
entry to the nucleus by a nuclear transporter protein. Once inside the
nucleus, 15-d-PGJ2 can bind to and activate peroxisome proliferatoractivated receptor γ (PPAR-γ) to regulate gene transcription. There is
also an unidentified mechanism by which 15-d-PGJ2 mediates
transcription in a PPAR-γ-independent manner.
through another cytoplasmic prostaglandin receptor.
For example, the chemoattractant receptor on Th2
cells (CRTH2) – a recently discovered G-proteincoupled receptor expressed on Th2 cells, basophils and
eosinophils – binds both PGD2 and 15-d-PGJ2.
Binding of ligand results in the release of intracellular
calcium, as opposed to the increase in cAMP that
occurs when PGD2 binds to its traditional receptor
[50]. However, the mechanism of action of 15-d-PGJ2
is unclear at best, might vary from system to system
and must be evaluated further.
∆12,14-PGJ2 in disease
15-deoxy-∆
Although 15-d-PGJ2 is implicated in the regulation of
many immune functions and disorders, here, we focus
on the role of this lipid in inflammation and cancer.
Inflammation
15-d-PGJ2 is emerging as a key anti-inflammatory
mediator. For example, 15-d-PGJ2 inhibits the
production of iNOS, TNF-α and IL-1β by mouse and
human macrophages [49,51]. The mechanism
involves the inhibition of mitogen-activated protein
(MAP) kinases, NF-κB or IκB kinase. Also, 15-d-PGJ2
can induce the apoptosis of mouse T and B cells, a
potential mechanism to down-regulate an
inflammatory immune response [45,52]. In addition,
many in vivo studies support a role for 15-d-PGJ2 as
an anti-inflammatory agent. 15-d-PGJ2 and PPAR-γ
Review
TRENDS in Immunology Vol.23 No.3 March 2002
ligands inhibit inflammation in models of
ischemia–reperfusion injury [53], colitis [54] and
adjuvant-induced arthritis [55], to name a few. There
is some evidence, however, that 15-d-PGJ2 can
promote inflammation also. 15-d-PGJ2 can induce
expression of the proinflammatory mediators type II
secreted phospholipase A(2) and cyclooxygenase 2 in
smooth muscle and epithelial cells, respectively
[56,57]. Also, 15-d-PGJ2 can stimulate the production
of proinflammatory mediators, such as IL-8 and
mitogen-activated protein kinases, in some systems
[58–60]. In vivo evidence from Thieringer et al. [61]
showed that 15-d-PGJ2 and PPAR-γ agonists induce
the production of TNF-α and IL-6 in LPS-treated
db/db mice. Therefore, the role of 15-d-PGJ2 in the
regulation of inflammation is complex and remains
under intense investigation.
Cancer
Acknowledgements
This research was
supported by USPHS
grants DE11390, HL56002,
HL007216,
5-T32DE07061-21,
T32HL66988, ES01247
and EY08976, the
James P. Wilmot Cancer
Center Discovery Fund
and Cystic Fibrosis
Foundation grant
CFF0020.
Unlike PGE2, which is involved clearly in the
promotion and persistence of carcinogenesis,
15-d-PGJ2 is emerging as a potent anti-tumor agent.
There are reports of the inhibition of tumor-cell growth
both in vitro and in vivo by 15-d-PGJ2 in a variety of
tissues, including breast, prostate, colon, lung, bladder
and esophagus [62,63]. 15-d-PGJ2 acts in a myriad of
ways to inhibit tumorigenesis. In most types of cancer,
for example, 15-d-PGJ2 acts on tumor cells directly by
inhibiting proliferation and stimulating apoptosis. The
mechanism in several cases, such as in bladder and
esophageal cancers, seems to be by the inhibition of
cyclin D1, which results in cell-cycle arrest [62,64,65]
and ultimately, apoptotic cell death (Fig. 5). The
induction of tumor-cell apoptosis by 15-d-PGJ2 occurs
generally through a PPAR-γ-mediated pathway,
because agonists for this nuclear receptor also inhibit
carcinogenesis. In addition, Sarraf et al. [66] found
that colon cancer patients have ‘loss of function’
mutations in PPAR-γ, further supporting a role for this
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