TRENDS in Immunology Vol.23 No.3 March 2002

http://immunology.trends.com 1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)02154-8

144 ReviewReview

Sarah G. Harris

Josue Padilla

Laura Koumas

Denise Ray

Depts of Microbiologyand Immunology and theJames P. Wilmot CancerCenter,Richard P. Phipps*

Depts of Microbiologyand Immunology,Environmental Medicine,Pediatrics, and Obstetricsand Gynecology, and theJames P. Wilmot CancerCenter, University ofRochester School ofMedicine and Dentistry,601 Elmwood Avenue,Rochester, NY 14642,USA.*e-mail: Richard_Phipps@urmc.rochester.edu

Interest in the ability of prostaglandin E2 (PGE2) toregulate the immune system has exploded in the pastdecade. Many new and exciting data have emergedconcerning the role of PGE2 in cells of the immunesystem and disease states. In this review, we willprovide highlights of that research, focusing first onthe interactions of PGE2 with T cells, B cells andantigen-presenting cells (APCs). Second, the role ofPGE2 in two disease states that have strong immunecomponents – periodontal disease and cancer – will bediscussed. Finally, we will summarize the effects of anewly discovered and prominent prostaglandin,15-deoxy-∆12,14-PGJ2 (herein referred to as 15-d-PGJ2), on the immune system. The volume ofliterature describing the roles of this lipid hasincreased exponentially in recent years. We willreview the actions of 15-d-PGJ2 on cells andspecifically, its effects on inflammation and cancer.

Prostaglandins

Prostaglandins are small lipid molecules thatregulate numerous processes in the body, includingkidney function, platelet aggregation,neurotransmitter release and modulation of immunefunction [1,2]. The production of prostaglandinsbegins with the liberation of arachidonic acid frommembrane phospholipids by phospholipase A2 inresponse to inflammatory stimuli. Arachidonic acid isconverted to PGH2 by the cyclooxygenase enzymesCOX-1 and COX-2 (known formally as prostaglandinendoperoxide H synthases). Generally, it is thoughtthat COX-1 is expressed constitutively in most tissuesof the body and acts to maintain homeostaticprocesses, such as mucus secretion. COX-2, bycontrast, is mainly an inducible enzyme and isinvolved primarily in the regulation of inflammation[3]. The recent development of COX-1- and COX-2-knockout mice has provided much informationconcerning the roles of these enzymes indevelopment, inflammation and carcinogenesis [4,5].

Cell-specific prostaglandin synthases convert PGH2into a series of prostaglandins, including PGI2, PGF2α,PGD2 and PGE2 (Fig. 1). The recent discovery that theexpression of PGE synthases can be induced byproinflammatory stimuli provides another layer ofregulation and complexity in the production ofprostaglandins [6]. Upon production, prostaglandinsare released rapidly from cells and act near their siteof production by binding to specific, high-affinityreceptors on plasma membranes [7].

PGE2

One of the best known and most well-studiedprostaglandins is PGE2. PGE2 is produced by manycells of the body – including fibroblasts, macrophagesand some types of malignant cells – and exerts itsactions by binding to one (or a combination) of its foursubtypes of receptor (EP1, EP2, EP3 and EP4). In themouse, the EP3 subtype consists of three differentisoforms, termed α, β and γ, and there are seven EP3splice variants in humans identified to date. Thereceptors are rhodopsin-type receptors containing

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

prostaglandin E2

(PGE2) and the PGD

2metabolite 15-deoxy-∆∆12,14-PGJ

2, and

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.

TRENDS in Immunology

Membrane phospholipids

Arachidonic acid

Phospholipase A2

COX-2COX-1LPSIL-1

TNF-αProstaglandin H2

Prostaglandin synthases

PGI2

PGD2

PGF2α

COOH

O

OH OH

O

COOH

15-d-PGJ2

PGE2

+

Fig. 1. Pathway of prostaglandin production. Arachidonic acid isliberated from membranes by phospholipase A2. The cyclooxygenaseenzymes (COX-1 and COX-2) produce prostaglandin H2 (PGH2) fromarachidonic acid. PGH2 is acted upon by prostaglandin synthases toproduce 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.

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145Review

seven hydrophobic transmembrane domains, coupledthrough their intracellular sequences to specificG proteins with different second messenger signalingpathways [8] (Fig. 2). The regulation of expression ofthe various subtypes of EP receptors on cells byinflammatory agents, or even PGE2 itself, enablesPGE2 to affect tissues in a very specific manner [7,9].Although knockout mice for all four EP receptors havebeen produced, no functional analysis of the effects onlymphocytes has been performed [10]. Recently,several reports have documented the expression offunctional EP receptors (EP1, EP3 and EP4) on thenuclear membranes of cells [11]. For example, EP3γand EP4 have been localized to the nuclear envelope ofendothelial cells. The receptors are functional,because they can modulate transcription, includingthat of the gene encoding inducible nitric oxidesynthase (iNOS) [11]. The discovery of nuclear EPreceptors provides an additional level to thePGE2-mediated regulation of cells, and further studyis necessary to determine the processes that governthe expression and function of the nuclear-localizedreceptors.

T cellsPGE2 has diverse effects on the regulation andactivity of T cells. The majority of research on T cellshas focused on CD4+ cells, for which work hasconcentrated on the roles of PGE2 in the modulationof proliferation, apoptosis and cytokine production.The inhibition of T-cell proliferation by PGE2 is wellestablished and currently, there is intense study todetermine the mechanism of inhibition. Ruggeri et al.[12] showed that the inhibition of proliferation isowing, in part, to the inhibition of polyaminesynthesis (i.e. spermine). PGE2 has been found also toinhibit intracellular calcium release [13] and theactivity of p59 (fyn) protein tyrosine kinase [14]; both

of these effects could be responsible for the observeddecrease in proliferation. Interestingly, EP receptorshave been implicated also in the inhibition ofproliferation owing to a decrease in the secretion ofinterleukin-2 (IL-2). During mucosal inflammation,for example, mucosal T cells up-regulate theirexpression of certain EP receptors (e.g. EP4), andthere is a resulting decrease in the T-cell productionof IL-2 [15]. Therefore, although much research hasbeen carried out to account potentially for thedecrease in proliferation of T cells caused by PGE2,further examination to find a definitive mechanism iswarranted.

The effects of PGE2 on the apoptosis of T cells aredependent on the maturation and activation state ofthe cell. PGE2 induces CD4+CD8+ double-positivethymocytes to undergo apoptosis both in vitro andin vivo [16]. In resting mature T cells, PGE2 inducesapoptosis also, which is associated with an increase inthe expression of c-Myc [17]. By contrast, PGE2protects T cells from T-cell receptor (TCR)-mediatedactivation-induced cell death by modulating theexpression of Fas ligand (FasL) on the T-cell surface.PGE2 decreases FasL mRNA and protein expression,which inhibits apoptosis [18]. Therefore, the inductionof apoptosis by PGE2 is involved in the selection ofimmature thymocytes, thus shaping the T-cellrepertoire. In addition, PGE2 regulates differentiallythe activities of mature resting and activated T cellsby inducing and inhibiting apoptosis, respectively.

PGE2 has a profound effect on the production ofcytokines by T cells. Recently, PGE2 has beenimplicated in the enhancement of T helper 2(Th2)-type responses. For example, PGE2 has noeffect on or enhances the production of Th2 cytokines,such as IL-4, IL-5 and IL-10, by Th2 cells, but inhibitsdrastically the production of Th1 cytokines, such asinterferon γ(IFN-γ)and IL-2, by Th1 cells [19] (Fig. 3).The induction of the Th2 response by PGE2 ismediated most probably by cAMP, because elementsthat increase the level of cAMP mimic the effects ofPGE2 [2]. Although a few reports suggest that PGE2inhibits Th2 responses [20], the vast majority ofreports shows that primarily, PGE2 has aTh2-inducing activity on T cells. Harnessing theability of PGE2 to modulate Th responses and thus,immunity in general could be extremely beneficial fortreating the numerous disorders in which there is adysregulated Th response.

Although less is known about the effects of PGE2on 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, PGE2decreases the production of IFN-γby CD8+ T-cellclones through a cAMP-dependent pathway [22].Such inhibition of IFN-γproduction is consistent withthe dogma that PGE2 favors type-2 responses ingeneral. Therefore, PGE2 plays a variety of crucialroles throughout the life of T cells, from the regulationof positive and negative selection in the thymus to the

Review

TRENDS in Immunology

EP1 EP2 EP4

AC AC

PKA

ATP

cAMP

cAMP

PLCGq/p

PIP2

Ca2+

Ca2+

DAG

IP3PKC

GiGs Gs

Gene regulation

EP3α, β and γ

Fig. 2. Prostaglandin E2 receptor (EP-R) signaling pathways. EP-Rs are rhodopsin-type receptors withseven transmembrane-spanning domains. The four main subtypes of EP-R (EP1–EP4) are coupled todifferent 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 coupledto Gs proteins and induce the expression of cAMP, which leads to gene regulation. The three isoformsof EP3 (α, β and γ) are coupled primarily to Gi and are most often inhibitory to cAMP. (There is someevidence that additional signaling cascades might be activated by EP3 binding.) Abbreviations: AC,adenylate cyclase; DAG, diacylglycerol; IP3, inositol triphosphate; PIP2, phosphatidylinositoldiphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.

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regulation of proliferation, apoptosis and cytokineproduction of mature cells.

B cellsPGE2 plays an important role in the development andactivity of B cells. In contrast to its effects on matureB cells, PGE2 acts in an inhibitory manner onimmature and developing B cells. For example, PGE2suppresses the proliferation of immature B cells, buthas no effect on, or even sometimes enhances, theproliferation of mature B cells [23]. Also, PGE2 is apotent inducer of immature B-cell apoptosis, but doesnot induce cell death in mature B cells [24]. In addition,B cells isolated from neonatal mice are susceptible toPGE2-induced apoptosis, whereas B cells from maturemice are unaffected [24]. Further evidence from thestudies of Shimozato and Kincade [25] confirms theinhibitory role of PGE2 in B-cell development; micetreated with PGE2 have fewer B-lineage precursors intheir bone marrow (BM) than untreated mice, whichimplicates PGE2 as a regulator of the elimination ofself-reactive or defective B-cell precursors.

PGE2 regulates the activity of mature B cells byinhibiting certain activation events but enhancingIg-class switching. Treatment of lipopolysaccharide(LPS)- and IL-4-activated B cells with PGE2 inhibitscell enlargement, MHC class II hyperexpression andexpression 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 theexpense of IgG3 and IgM) in LPS- and IL-4-stimulatedB cells by a cAMP-dependent mechanism [26]. Thisinduction of expression of IgE and IgG1 by PGE2 againsupports the theory that PGE2 acts predominantly toinduce Th2 responses (Fig. 3). Although not yet showndirectly, this implies a role for PGE2 in enhancing thedevelopment of allergy and asthma. In addition tobeing responsive to PGE2, an unusual B-lineage cell,called the B/macrophage, expresses the cyclooxygenaseenzymes and can produce PGE2 upon stimulation [27].The PGE2 produced by the B/macrophage can act onother immune cells (such as T cells) to further inducetype-2 immune responses. Therefore, B-lineage cellsmodulate immune responses by both producing andresponding to PGE2.

Antigen-presenting cellsAPCs play a key role in B- and T-cell-mediatedimmune responses. PGE2 modulates the activities of‘professional’APCs, such as dendritic cells (DCs) andmacrophages, in a variety of ways. Immature DCstake up antigen in peripheral tissues, which inducestheir activation and subsequent migration tolymphoid organs. In the lymph nodes, DCs matureinto cells able to present antigen to and prime T cells.PGE2 has been suggested to play a key role in theseevents. PGE2 has both stimulatory and inhibitoryeffects on the activation of DCs, depending on the siteof encounter. In peripheral tissues, PGE2 seems tohave a stimulatory effect on DCs, inducing theiractivation. Once the cells have migrated to lymphoidorgans, PGE2 assumes an inhibitory role, inhibitingthe maturation of DCs and their ability to presentantigen [28]. Also, PGE2 regulates the production ofcytokines by DCs, thus shaping the subsequentimmune response. For example, if PGE2 is presentduring the priming of DCs with antigen, the DCs areinhibited 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 differentiationof naive T cells into Th2 cells directly – the T cellsproduce high levels of IL-4 and no IFN-γ. This furthersupports the role of PGE2 in biasing the immunesystem towards Th2 and away from Th1 responses.Furthermore, BM-derived DCs can produce PGE2themselves [28] and thus, autoregulate theirfunctions in the immune system.

Another established function of PGE2 is theregulation of cytokine production by activatedmacrophages. The effects of PGE2 on macrophagesare suppressive for type-1 immune responses. PGE2down-regulates the expression of the IL-12 receptorand inhibits the production of tumor necrosisfactor α (TNF-α), IL-1β, IL-8 and IL-12 bymacrophages [30]. Similarly, PGE2 reduces theproduction of TNF-α by LPS-treated peritonealmacrophages [31]. Studies of zymosan-treatedmouse peritoneal macrophages show that PGE2causes a down-regulation of TNF-α production andan up-regulation of IL-10 production, through theEP2 and EP4 receptors [32]. Therefore, PGE2 acts toup-regulate type-2 responses in macrophages(Fig. 3). As for some DCs, PGE2 is produced in largequantities by macrophages, primarily in response toproinflammatory mediators, such as IL-1 and LPS[33]. Therefore, PGE2 might act as an autocrinefeedback regulator, because it has been shown topositively regulate its own expression byup-regulating the expression of COX-2.

PGE2

in disease

PGE2 plays an integral role in a myriad of infectionsand diseases. We have chosen to highlight twodiseases for which PGE2 has been shown to be centralto disease progression – periodontal disease andcertain cancers.

Review

TRENDS in Immunology

IL-4, IL-5, IL-10IL-2, IFN-γ

IgG1, IgE

TNF-α, IL-1β, IL-12, IL-12R

IL-10IL-12

PGE2

Mφ

DC

B cell

T cell

Fig. 3. Prostaglandin E2

(PGE2) enhances theproduction of type-2cytokines and antibodies.PGE2 acts on T cells toenhance their productionof interleukin-4 (IL-4), IL-5and IL-10, but inhibitstheir production of IL-2and interferon γ (IFN-γ).Acting on B cells, PGE2

stimulates isotype-classswitching to induce theproduction of IgG1 andIgE. PGE2 acts on antigen-presenting cells, such asmacrophages (Mφs) anddendritic cells (DCs), toinduce the expression ofIL-10 and inhibitexpression of IL-12, IL-12receptor (IL-12R), tumornecrosis factor α (TNF-α)and IL-1β. The overallresult is an enhancementof T helper 2 (Th2)responses and inhibitionof Th1 responses by PGE2.

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147Review

Periodontal diseasePeriodontitis is a chronic inflammatory process thatdegrades the tooth support structures (i.e. gingiva,periodontal ligament, cementum and alveolar bone).Periodontal disease is thought to be induced by theaccumulation of bacterial plaque at the gum line. Thepresence of bacterial plaque in the gingival creviceelicits a complex bacteria–host interaction, whichleads to the degradation of connective tissue, alveolarbone destruction and eventually, tooth loss. The hostresponds to bacterial endotoxins (e.g. LPS) bystimulating cells present in the periodontal tissues torelease proinflammatory mediators, such as IL-1β,TNF-α and PGE2 (Fig. 4). It is the local action ofprostaglandins and cytokines, which play crucialroles in the inflammatory process, that leads to thepathology associated with periodontal disease.

Since the early 1970s, PGE2 has been used as abiochemical marker for periodontitis, becauseinflamed periodontal tissues have high levels of PGE2[34]. PGE2 causes increased vasopermeability andvasodilation, leading to redness and edema. Also,PGE2 induces the synthesis of matrixmetalloproteinases (MMPs) by infiltrating andresident cells, such as monocytes and fibroblasts,respectively. MMPs cause connective-tissuedegradation and osteoclastic bone destruction, both ofwhich are hallmarks of periodontal disease [35].Owing to the high-level expression of PGE2 and itsdetrimental effects in the periodontium, there arenumerous models of periodontal disease in animalsand humans evaluating the effectiveness ofcyclooxygenase inhibitors. The suppression of PGE2synthesis by these drugs diminishes greatly the lossof periodontal connective tissue [34,36]. Thus, thesedata indicate not only an association between diseaseactivity and levels of PGE2 within tissues, but thateliminating PGE2 with cyclooxygenase inhibitors(e.g. the COX-2-selective inhibitor Vioxx) leads to a

concomitant reduction of periodontal diseaseprogression (Fig. 4).

CancerThe relationship between enhanced cyclooxygenaseexpression and selected cancers is becoming wellestablished (for review, see Ref. [37]). Over-expressionof COX-2 has been noted in many cancers, including,but not limited to, cancers of the breast, colon andprostate [37]. The discovery that the inhibition ofCOX activity inhibits cancerous tumor growth inmany systems has further solidified our knowledge ofthe integral role that cyclooxygenases play in tumorprogression. Key epidemiological studies reveal thatinhibiting the cyclooxygenase enzymes reduces theincidence of certain cancers. For example, individualstaking 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 tumorigenesisis under intense investigation also.

PGE2, which promotes tumor-cell survival, hasbeen found at higher concentrations in tumor tissuesthan normal tissues [38]. PGE2 mediates tumorsurvival by several mechanisms. It inhibits tumor-cell apoptosis and induces tumor-cell proliferation[39]. Also, PGE2 increases tumor progression byaltering cell morphology, and increasing cell motilityand migration [40]. In addition to the direct effects ofPGE2 on tumor cells, this lipid mediator induces theproduction of metastasis-promoting MMPs andstimulates angiogenesis [40] (Fig. 5). PGE2 acts alsoas an immunomodulator (as described earlier), topromote humoral and Th2-type immune responsesthat do not favor tumor destruction, and inhibitTh1-type responses that do favor tumor destruction.Therefore, the relationship between PGE2 and tumorprogression is quite important, and further study inthe field is warranted to understand the additionalroles of this lipid. In the future, specific inhibition ofPGE2 by the inhibition of PGE synthases, forexample, might prove extremely beneficial for theabrogation of tumor progression.

15-deoxy-∆∆12,14-PGJ2

The J series of prostaglandins, once thought tocomprise inactive degradation products of PGD2, isnow well established as regulating diverse processes,such as adipogenesis, inflammation andtumorigenesis. 15-d-PGJ2 is the end-productmetabolite of PGD2 and is produced by a variety ofcells, including mast cells, T cells, platelets andalveolar macrophages. The exact mechanism of entryof 15-d-PGJ2 into cells is unknown, but it is possiblethat 15-d-PGJ2 enters by an active transport systemsimilar to those described by Narumiya’s group forother cyclopentanone prostaglandins (e.g. ∆-12 PGJ2)[41]. Once inside the cell, an additional crypticmechanism allows transport of the cyclopentanoneprostaglandins into the nucleus, where they affect

Review

TRENDS in Immunology

COX-2 PGE2

Bacterialproducts

Healthyperiodontium

MΦ

TNF-α MMPs

MMPs

Alveolar boneresorption

Extracellularmatrix

destruction

Tooth lossPeriodontitisFibroblast

LPS

IL-1

Fig. 4. Prostaglandin E2 (PGE2) is a biochemical marker for and key element in the pathogenesis ofperiodontal disease. Lipopolysaccharide (LPS) from periodontopathogenic bacteria elicits a complexbacteria–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 inducesincreases in vasopermeability and vasodilation, leading to redness and edema. PGE2 is also a potentinducer 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 thedegradation of connective tissue, alveolar bone destruction and eventually, tooth loss. EliminatingPGE2 with cyclooxygenase inhibitors modulates the host’s overt response to the bacteria, thusreducing periodontal disease progression.

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148 Review

gene transcription (Fig. 6). Although it has never beenshown directly that 15-d-PGJ2 uses thesetransporters, its similar structure to the otherprostaglandins makes this mechanism feasible. It ispossible also that locally produced PGD2 could enter acell by an anionic transporter molecule and then bedegraded to 15-d-PGJ2 once inside the cytoplasm [42].These mechanisms are not, of course, mutuallyexclusive. Once inside the cell, 15-d-PGJ2 wasthought traditionally to exert its effects by binding tothe peroxisome proliferator-activated receptor γ(PPAR-γ) [43]. PPARs are a family of ligand-activatednuclear transcription factors, which, upon the bindingof ligand, form a heterodimer with the retinoicX receptor. This complex then binds to PPAR-responsive elements (PPREs) in the promoter regionsof target genes [43]. PPAR-γwas found initially inadipose tissue, where it plays a key role in theregulation of adipogenesis. More recently, thereceptor has been found also in many immune cells,including neutrophils, macrophages, T cells andB cells [44].

There has been recent controversy over the linkbetween the action of 15-d-PGJ2 and PPAR-γbinding.Initial reports focused on the ability of 15-d-PGJ2 tobind to and activate PPAR-γ. For example, 15-d-PGJ2inhibits T-cell proliferation and induces apoptosis ofT cells by a PPAR-γ-dependent mechanism [45,46].More recently, however, evidence has shown thatthere are also effects of 15-d-PGJ2 that areindependent of PPAR-γactivation (Fig. 6). Forexample, 15-d-PGJ2 can down-regulate the productionof iNOS by microglial cells through PPAR-γ-independent mechanisms [47]. Vaidya and colleagueshave shown that 15-d-PGJ2 can inhibit the productionof oxygen free radicals by neutrophils in a PPAR-γ-independent manner [48]. Additionally, the inhibitionof IκB kinase can occur through PPAR-γ-independentmeans [49]. Although the exact mechanism of15-d-PGJ2 action in these systems is unknown, it hasbeen postulated that 15-d-PGJ2 could be acting

through another cytoplasmic prostaglandin receptor.For example, the chemoattractant receptor on Th2cells (CRTH2) – a recently discovered G-protein-coupled receptor expressed on Th2 cells, basophils andeosinophils – binds both PGD2 and 15-d-PGJ2.Binding of ligand results in the release of intracellularcalcium, as opposed to the increase in cAMP thatoccurs when PGD2 binds to its traditional receptor[50]. However, the mechanism of action of 15-d-PGJ2is unclear at best, might vary from system to systemand must be evaluated further.

15-deoxy-∆∆12,14-PGJ2

in disease

Although 15-d-PGJ2 is implicated in the regulation ofmany immune functions and disorders, here, we focuson the role of this lipid in inflammation and cancer.

Inflammation15-d-PGJ2 is emerging as a key anti-inflammatorymediator. For example, 15-d-PGJ2 inhibits theproduction of iNOS, TNF-α and IL-1β by mouse andhuman macrophages [49,51]. The mechanisminvolves the inhibition of mitogen-activated protein(MAP) kinases, NF-κB or IκB kinase. Also, 15-d-PGJ2can induce the apoptosis of mouse T and B cells, apotential mechanism to down-regulate aninflammatory immune response [45,52]. In addition,many in vivo studies support a role for 15-d-PGJ2 asan anti-inflammatory agent. 15-d-PGJ2 and PPAR-γ

Review

TRENDS in Immunology

Cyclooxygenases

PGE2

PGD2

15-d-PGJ2

ProliferationProliferation

Apoptosis

MMPs

MMPs

Apoptosis

Key:

Apoptotic bleb

MMP

Tumor cell

Tumor promotion Tumor inhibition

Fig. 5. Opposing effectsof prostaglandin E2 (PGE2)and 15-deoxy-∆12,14-PGJ2

(15-d-PGJ2) on tumorcells. PGE2 and 15-d-PGJ2

have opposite effects onmalignant-celldevelopment. PGE2

promotes some types ofcancers by inducing theproduction of matrixmetalloproteinases(MMPs), leading toenhanced metastasis.PGE2 also induces cancer-cell proliferation andinhibits apoptosis. Bycontrast, 15-d-PGJ2

inhibits tumor formation.15-d-PGJ2 decreasesMMP production, inhibitsmalignant-cellproliferation andstimulates apoptosis.

TRENDS in Immunology

PGD2

15-d-PGJ2

15-d-PGJ2

Cytoplasm

PGD2

15-d-PGJ2

Anioniccarrierprotein

15-d-PGJ2receptor?

Activetransportsystem

Nucleartransporter

Binds to PPAR-γand regulatestranscription

Other mechanismsto regulatetranscription

Nucleus

Fig. 6. Possible modes of action of 15-deoxy-∆12,14-PGJ2 (15-d-PGJ2) inthe 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, andthen enter the nucleus by a nuclear transporter, as described for othercyclopentanone prostaglandins. Also, 15-d-PGJ2 could bind to anundiscovered cytoplasmic receptor. Alternatively, PGD2 could gainentry into the cell by means of an anionic carrier protein, and then bemetabolized in the cytoplasm to 15-d-PGJ2. 15-d-PGJ2 could then gainentry to the nucleus by a nuclear transporter protein. Once inside thenucleus, 15-d-PGJ2 can bind to and activate peroxisome proliferator-activated receptor γ (PPAR-γ) to regulate gene transcription. There isalso an unidentified mechanism by which 15-d-PGJ2 mediatestranscription in a PPAR-γ-independent manner.

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149Review

ligands inhibit inflammation in models ofischemia–reperfusion injury [53], colitis [54] andadjuvant-induced arthritis [55], to name a few. Thereis some evidence, however, that 15-d-PGJ2 canpromote inflammation also. 15-d-PGJ2 can induceexpression of the proinflammatory mediators type IIsecreted phospholipase A(2) and cyclooxygenase 2 insmooth muscle and epithelial cells, respectively[56,57]. Also, 15-d-PGJ2 can stimulate the productionof proinflammatory mediators, such as IL-8 andmitogen-activated protein kinases, in some systems[58–60]. In vivo evidence from Thieringer et al. [61]showed that 15-d-PGJ2 and PPAR-γagonists inducethe production of TNF-α and IL-6 in LPS-treateddb/db mice. Therefore, the role of 15-d-PGJ2 in theregulation of inflammation is complex and remainsunder intense investigation.

CancerUnlike PGE2, which is involved clearly in thepromotion and persistence of carcinogenesis,15-d-PGJ2 is emerging as a potent anti-tumor agent.There are reports of the inhibition of tumor-cell growthboth in vitro and in vivo by 15-d-PGJ2 in a variety oftissues, including breast, prostate, colon, lung, bladderand esophagus [62,63]. 15-d-PGJ2 acts in a myriad ofways to inhibit tumorigenesis. In most types of cancer,for example, 15-d-PGJ2 acts on tumor cells directly byinhibiting proliferation and stimulating apoptosis. Themechanism in several cases, such as in bladder andesophageal cancers, seems to be by the inhibition ofcyclin D1, which results in cell-cycle arrest [62,64,65]and ultimately, apoptotic cell death (Fig. 5). Theinduction of tumor-cell apoptosis by 15-d-PGJ2 occursgenerally through a PPAR-γ-mediated pathway,because agonists for this nuclear receptor also inhibitcarcinogenesis. In addition, Sarraf et al. [66] foundthat colon cancer patients have ‘loss of function’mutations in PPAR-γ, further supporting a role for this

receptor in the inhibition of tumor growth. The over-expression of PPAR-γin many cancers suggests apossible therapeutic use for 15-d-PGJ2 and otherPPAR-γligands [67].

Aside from inducing apoptosis in tumor cells,15-d-PGJ2 and PPAR-γ ligands can also inhibittumorigenesis by inducing the differentiation oftumor cells [68]. The anti-tumor activity of 15-d-PGJ2is, however, not restricted to the direct inhibition oftumor cells. 15-d-PGJ2 acts also on surrounding cells,such as endothelial cells, inhibiting their expressionof the vascular endothelial growth factor receptor(VEGFR), which results in the inhibition ofangiogenesis in vivo [69]. Also, 15-d-PGJ2 candown-regulate the expression of MMP-9 in vascularsmooth muscle cells, which results in the inhibition oftissue destruction and a subsequent inhibitory effecton the migration of cells [70]. Therefore, 15-d-PGJ2, incontrast to PGE2, inhibits tumor formation byinducing the apoptosis of tumor cells and inhibitingtumor-cell migration and angiogenesis.

Conclusions

The roles of PGE2 and 15-d-PGJ2 in the immunesystem are diverse and complex. Both mediators haveprofound, and opposing, effects on tumorigenesis andare key regulators of inflammation. Owing to the factthat these two lipids are produced from the sameprecursor (arachidonic acid) by the samecyclooxygenase enzymes, additional means toregulate the production of one or the otherprostaglandin must exist. Prime candidates are theprostaglandin synthases, which synthesize specificprostaglandins from the PGH2 precursor. Therefore,future study into the function of these synthases andregulation of the synthase-encoding genes will leadprobably to new approaches for the treatment and,perhaps, prevention of immune disorders, rangingfrom inflammation to cancer.

Review

Acknowledgements

This research wassupported by USPHSgrants DE11390, HL56002,HL007216,5-T32DE07061-21,T32HL66988, ES01247 and EY08976, the James P. Wilmot CancerCenter Discovery Fundand Cystic FibrosisFoundation grantCFF0020.

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