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Published online before print October 17, 2006
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* Department of Asthma, Allergy and Respiratory Science, King’s College London, Guy’s Hospital, London, UK;
Leukocyte Biology Section, National Heart and Lung Institute, Imperial College, London, UK; and
Academic Unit of Respiratory Medicine, School of Medicine and Biological Sciences, University of Sheffield, UK
1 Correspondence: Department of Asthma, Allergy and Respiratory Science, King’s College London, 5th Floor Thomas Guy House, Guy’s Hospital, London SE1 9RT, UK. E-mail: Hilary.sandig{at}kcl.ac.uk
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ABSTRACT |
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 TOP ABSTRACT PGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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Key Words: CRTH2 • DP • 15d-PGJ2 • inflammation and allergic disease
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PGD2 AS A PRO- AND ANTI-INFLAMMATORY MEDIATOR |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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PGD2 is a relatively unstable molecule, which is readily degraded by a series of spontaneous dehydration and isomerization reactions in vitro and also by enzymatically catalyzed reactions in vivo to a wide variety of metabolites, containing the D-ring of PGD2, the F-ring, or the J-ring (Fig. 1
) [7
, 8
]. Several of these metabolites are now known to be bioactive, and the J series of PGD2 metabolites, PGJ2, 
12-PGJ2, and 15d-PGJ2, is of particular interest, as it has been implicated as the mediators of many of the anti-inflammatory effects of PGD2 [10
, 11
]. PGD2 and 15d-PGJ2 production was observed during the resolution of carrageenin-induced pleural inflammation, and when this PG production was blocked with cyclooxygenase (COX) inhibitors, the inflammation worsened [10
]. Administration of PGD2 or 15d-PGJ2 to the animals treated with the COX inhibitor led to the resolution of the inflammation, providing strong evidence for a role for these metabolites in the resolution of inflammation in vivo [10
]. It was later observed by the same group that 15d-PGJ2 induces the apoptosis, first of infiltrating neutrophils and later, of the macrophages recruited to clear these apoptotic cells, thus aiding in the clearance of the inflammatory infiltrate [12
]. Evidence for an anti-inflammatory role for PGD2 and its metabolites was also generated in studies using mice deficient in an enzyme, which produces PGD2, hematopoietic PGD2 synthetase (H-PGDS) [11
]. The H-PGDS–/– animals show impaired resolution of inflammation, and animals transgenic for H-PGDS show a reduced inflammatory response [11
].
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PGD2 SIGNALING |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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s-type G protein [14
]. PGD2 has also been demonstrated to signal via other PG receptor family members, for example, causing bronchoconstriction via the thromboxane A2 receptor (TP receptor) [18
, 19
]. Compared with their wild-type littermates, DP-deficient mice develop less severe lung inflammation and airway hyper-reactivity in a model of antigen-induced airway inflammation, and expression of Th2-type cytokines is also decreased in the knockout animals [20 ]. In addition, the pharmacological blockade of DP has been shown to alleviate inflammation in several inflammatory models [21 , 22 ]. These results appear to imply that the receptor has a proinflammatory role in vivo; however, DP also appears to mediate anti-inflammatory responses. For example, specific activation of DP in a model of lung inflammation has been shown to limit the inflammatory response [23 ].
PGD2 signaling was complicated further by the discovery of a second PGD2 receptor, chemoattractant-receptor homologous molecule expressed on Th2 cells (CRTH2). Its existence had been postulated previously, following the observations that not all the effects of PGD2 on eosinophils were mediated by DP signaling [24 ]. For example, PGD2 induces eosinophil migration, CD11b up-regulation, L-selectin shedding, and actin polymerization—responses that are neither mimicked by a DP agonist nor prevented by a DP antagonist [24 ]. The then unidentified receptor, stimulatory for eosinophils but not neutrophils, was termed DP2 [24 ]. Around the same time, CRTH2 was identified independently in a screen for genes expressed by Th2 but not Th1 cells [25 ], and this orphan GPCR was later identified as a PGD2 receptor [26 ].
As DP2 and CRTH2 induce eosinophil migration in response to PGD2 and are expressed by eosinophils but not neutrophils, it was presumed that the proposed receptor, DP2, and CRTH2 were one and the same [24 , 26 ]. CRTH2/DP2 shares most homology with the chemoattractant receptors, and like DP/DP1, is expressed on several leukocyte types, including eosinophils, basophils, T lymphocytes, and monocytes [15 , 26 ]. DP and CRTH2 are activated by several of the PGD2 metabolites, although generally the metabolites are less potent at the GPCRs than PGD2 itself [9 , 27 28 29 30 ] (reviewed in ref. [31 ]).
CRTH2-deficient mice have been characterized recently in a model of airway inflammation [32 ]. Following sensitization to OVA, a single aerosol challenge, which did not induce significant leukocyte recruitment to the lungs of the wild-type mice, caused lung inflammation in the CRTH2-deficient animals [32 ]. Upon in vitro stimulation, splenocytes from the knockout mice produced greater levels of IL-5, and it was proposed that increased IL-5 production by these animals was the likely cause of the increased inflammation [32 ]. These results are surprising, however, as CRTH2 appears to have a stimulatory effect on leukocytes in vitro (as discussed below), and previous studies in animal models using CRTH2-selective agonists and antagonists have also demonstrated a proinflammatory role for the receptor [5 , 23 , 33 , 34 ].
In conclusion, the two PGD2 receptors, DP and CRTH2, are expressed by a variety of leukocytes [15 16 17 , 26 ] and have complex roles in inflammation, which have yet to be fully elucidated.
PGD2 signaling via nuclear receptors
The nuclear receptors are a large family of intracellular receptors, which modify gene expression, usually in a ligand-dependent manner. Several nuclear receptors are known to have roles in the immune system, for example, the glucocorticoid receptor (GR) binds natural steroids or steroidal drugs, leading to inhibitory effects on inflammation, largely by inhibiting gene expression. The peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors with known members, PPAR, PPAR
(or PPARß), and PPAR
. These receptors differ from GR in that they are believed to respond to locally produced ligands, but like GR, the PPARs are increasingly believed to have an important role in the immune system (recently reviewed in ref. [35
]).
PGD2, PGJ2, and 15d-PGJ2 have been shown to activate PPAR and PPAR [36
, 37
], although only at micromolar concentrations, and whether the PGs are the principal ligands of these receptors in vivo is the cause for much debate [38
]. Amongst leukocytes, PPAR is expressed by monocytes and macrophages [39
, 40
], eosinophils [41
, 42
], and T lymphocytes [43
], and as discussed below, the PGD2 metabolites may be able to induce signaling in these cells via PPAR activation.
PGD2 signaling by direct modification of proteins
The J series metabolites of PGD2 contain a cyclopentenone ring and hence, are often referred to as the cyclopentenone PGs. The ,ß-unsaturated carbonyl ring contains a chemically reactive carbon, which is believed to be capable of forming adducts with free thiols in proteins by Michael addition (Fig. 2
) [44
]. It is thought that the J series of PGs can enter cells, possibly via a PG transporter [46
], and interact directly with free cysteine residues in proteins, modifying protein function. For example, it has been demonstrated that 15d-PGJ2 is able to inhibit NF-
B signaling by interacting directly with cysteine residues in IB kinase [47
] and NF-B itself [48
]. 15d-PGJ2 also inhibits AP-1 activity, again, by covalent modification of a specific cysteine residue within the protein [49
]. It is believed that the conjugated ring system and electronegative oxygen result in a slightly positive carbon, which can then participate in a Michael addition with a free thiol, such as that on a cysteine side-chain (Fig. 2)
. Indeed, 15d-PGJ2 has been shown to form adducts with numerous cellular proteins via a reaction that is dependent on the presence of the double bond within the PG ring [50
].
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B signaling by PGD2 is relevant in vivo, as these animals showed increased NF-B signaling compared with wild-type controls [11
]. Supportive of this, transgenic animals, overexpressing H-PGDS, exhibited less NF- B activity than the wild-type mice [11
].
Therefore, directly or via the production of its metabolites, PGD2 appears to have the potential to signal via the cell surface receptors—DP, other PG receptor family members, or CRTH2—via the nuclear receptors, PPAR and PPAR, or to modify signaling by direct interaction with intracellular proteins such as NF-B. By focusing on the effects of PGD2 signaling in different leukocytes, this review aims to clarify the ability of PGD2 and its metabolites to impact the immune system via its receptors and the modification of other signaling pathways.
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PGD2 AND T LYMPHOCYTES |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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The DP receptor is expressed by T lymphocytes and has been shown to inhibit the production of the Th1 cytokine IFN- by these cells in vitro, which may also skew the immune system to a more Th2-type response [16
]. Therefore, PGD2 signaling on T lymphocytes provides an important mechanism, linking the recruitment of Th2 cells, the expression of Th2 cytokines, and the inhibition of Th1 cytokine expression [16
, 26
]. Furthermore, these data imply that PGD2-induced signaling represents a plausible target for the treatment of allergic disease.
In contrast to the activation phenotype induced by PGD2 in T lymphocytes, the PGD2 metabolite, 15d-PGJ2, has been shown to inhibit T lymphocyte proliferation, and it is presumed that this effect is mediated by PPAR, as it is mimicked by the PPAR agonists, ciglitazone, troglitazone, BRL49653, and pioglitazone [43
, 55
]. This response is in opposition to the CRTH2-mediated, proinflammatory effects of PGD2 on T lymphocytes. It is interesting to note, however, that the effects are seen at quite different ligand concentrations: PGD2 was reported to induce maximal T lymphocyte migration at a concentration of 25 nM [26
], whereas the inhibition of proliferation seen with the PGD2 metabolite 15d-PGJ2 occurred only with micromolar concentrations of the PG [43
, 55
] (Table 1
). Therefore, only when PGD2 is produced in large amounts are there likely to be sufficient concentrations of its metabolites available to activate PPAR, thus inhibiting T lymphocyte proliferation and consequently, the inflammatory response. In contrast, if only nanomolar concentrations of PGD2 and its metabolites are produced, the PGs may be expected to activate T lymphocytes [16
, 26
].
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12-PGJ2, and 15d-PGJ2 are known to accelerate the apoptosis of many cells, although it appears that in different cells, different mechanisms are at work. For example, the PPAR antagonist, GW9662, is able to ablate the apoptosis induced by 15d-PGJ2 in chondrocytes [66
] but has no effect on the 15d-PGJ2-mediated apoptosis of a breast cancer cell line [67
]. PPAR agonists have no effect on T lymphocyte viability, implying that the PGD2 metabolites induce cell death in these cells, independently of the nuclear receptor [55
]. 15d-PGJ2 has been reported to induce the production of reactive oxygen species (ROS) in T lymphocytes and consequently, the loss of the mitochondrial membrane potential (
m) and the release of cytochrome c from the mitochondria [55
]. A scavenger of ROS was able to prevent the loss of m and the subsequent apoptosis induced by 15d-PGJ2 in Jurkat cells, and hence, it appears that the PG triggers the mitochondrial pathway of apoptosis via ROS production [55
]. The mechanism behind 15d-PGJ2-induced ROS production in T lymphocytes is unknown, but inhibition of the mitochondrial complex I has been linked to 15d-PGJ2-mediated ROS production in a breast cancer cell line [68
] and in isolated mitochondrion [69
]. Indeed, it has been shown that a classical inhibitor of complex I is able to inhibit 15d-PGJ2-induced ROS production, strongly implying that this complex is involved in the 15d-PGJ2-induced production of ROS [69
]. It may be that such a mechanism is at work in cyclopentenone-treated T lymphocytes.
In contrast to these findings [55
], Cippitelli et al. [56
] demonstrated that micromolar concentrations of 15d-PGJ2 reduced the apoptosis observed upon T lymphocyte activation by inhibiting Fas ligand (FasL) expression. The reduction in FasL expression is PPAR-independent, and it was suggested that the reactive cyclopentenone moiety of the PG was responsible for the inhibition of apoptosis [56
]. These findings are hard to reconcile with the study by Nencioni et al. [55
], however, where 15d-PGJ2 was shown to induce the apoptosis even of stimulated T lymphocytes.
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PGD2 ON GRANULOCYTES |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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Neutrophils do not express the novel PGD2 receptor, CRTH2, which is expressed by eosinophils and basophils [24 , 26 ], and as a result, nanomolar concentrations of PGD2 induce the selective migration of eosinophils and basophils in vitro [24 , 26 ] and the up-regulation of adhesion molecules on these cells [24 , 76 ]. It is surprising, however, that administration of PGD2 in vivo has been reported to induce neutrophil recruitment via CRTH2 [34 ]. A CRTH2-selective agonist, DK-PGD2, although unable to stimulate murine neutrophil recruitment ex vivo, caused neutrophil infiltration when administered into the epidermis, and the CRTH2 antagonist, ramatroban, inhibited neutrophil accumulation in a murine model of FITC-induced contact hypersensitivity [34 ]. Presumably, this surprising result is a result of an indirect effect of CRTH2 signaling on other cell types, possibly via the induction of a neutrophil-specific chemokine, such as murine CXCL1/keratinocyte-derived chemokine [34 ].
Nanomolar concentrations of 12-PGJ2 cause the release of eosinophils from guinea pig bone marrow [28
], and in rats, the CRTH2-selective agonist, DK-PGD2, was shown to induce blood eosinophilia, which was blocked by the CRTH2 antagonist, ramatroban [57
]. By signaling via CRTH2, PGD2 would therefore be expected to cause blood eosinophilia and to enhance inflammation in vivo. CRTH2 signaling in eosinophils has also been shown to increase the cells’ response to CCL11/eotaxin-1, providing a further mechanism to amplify inflammatory cell recruitment [28
, 58
]. In addition, CRTH2 activation has been shown to induce eosinophil respiratory burst [58
] and degranulation [17
]. Collectively, these data suggest that CRTH2 activation by PGD2 and its metabolites on granulocytes would be proinflammatory in vivo.
In addition to CRTH2, eosinophils and basophils also express the PGD2 receptor, DP [17
, 59
], allowing for the interesting possibility of receptor cross-talk between the two GPCRs. DP is coupled to a Gs-type G protein and thus signals in part via raising the intracellular levels of the secondary messenger cAMP [14
], whereas CRTH2 couples to a Gi G protein, which acts to inhibit cAMP production [26
], implying that the two receptors may exert antagonistic effects. Indeed, DP signaling has been demonstrated to inhibit the CRTH2-mediated CD11b up-regulation in eosinophils but not basophils [24
, 59
], and signaling through DP inhibits CRTH2-mediated basophil migration [59
]. This is in keeping with previous data, demonstrating that increases in intracellular cAMP in eosinophils, for example, after administration of phosphodiesterase 4 inhibitors such as rolipram, generally inhibit cell activation [77
78
79
80
]. By inhibiting CRTH2-induced cell migration and adhesion molecule expression, DP signaling appears to have an anti-inflammatory role in basophils and eosinophils.
Increased intracellular cAMP also prolongs eosinophil survival in vitro [81 ], and it has been demonstrated that a synthetic, DP-selective agonist increased the lifespan of eosinophils [17 ]. Such an effect would be expected to prolong the duration of inflammation, but PGD2 itself had no effect on eosinophil survival in parallel experiments, and there are no known naturally occurring agonists able to stimulate DP selectively [17 ]. CRTH2 has been demonstrated to be expressed at higher levels than DP in eosinophils [59 ], although both receptors bind PGD2 with similar affinity [26 , 82 ]; therefore, although it may be the case that the pro-survival effect of DP signaling is not physiologically relevant, it is possible that the response is simply not observed, as CRTH2 signaling is usually dominant. A situation can then be envisaged, whereby once CRTH2 expression is down-regulated, for example, after cell activation [16 ], a DP-mediated, anti-apoptotic signal could be uncovered.
The effects of PGD2 and its metabolites on granulocyte survival have been investigated further. Micromolar concentrations of PGD2 induce eosinophil but not neutrophil apoptosis, whereas similar concentrations of PGJ2, 12-PGJ2, and 15d-PGJ2 cause the apoptosis of both granulocyte types [61
]. Earlier studies about cell lines found that micromolar amounts of the PGD2 metabolites inhibit cellular proliferation [83
], and it was later demonstrated that the anti-proliferative properties of the PGD2 metabolite, 12-PGJ2, were the result of the lipid’s ability to induce apoptosis [84
]. Ward et al. [61
] showed that the PGD2 metabolites, PGJ2, 15d-PGJ2, and 12-PGJ2, induced granulocyte apoptosis, and speculated that PGD2 itself caused eosinophil and not neutrophil cell death, because the eosinophils accelerated the degradation of the PG to its proapoptotic metabolites. In support of this hypothesis, it has been demonstrated that eosinophils are capable of accelerating the degradation of micromolar concentrations of PGD2 by unknown mechanisms [85
].
15d-PGJ2-induced neutrophil apoptosis is independent of PPAR but dependent on caspases, and it was proposed that the PGs were causing apoptosis via the inhibition of NF-B [61
], which by alternative methods has been demonstrated to induce granulocyte apoptosis [86
87
88
]. 12-PGJ2 and 15d-PGJ2 inhibited NF-B inhibition in eosinophils and neutrophils, supporting this hypothesis [61
]. Basophil apoptosis is also accelerated by PGD2, by an unknown, CRTH2- and DP-independent mechanism [59
].
Although the induction of eosinophil apoptosis by the PGD2 metabolites appears to be PPAR-independent [61
], signaling by the nuclear receptor has been shown to affect other aspects of eosinophil biology. For example, synthetic PPAR agonists have been shown to have inhibitory actions on IL-5-induced survival and CCL11-induced migration of eosinophils [41
, 42
]. As micromolar concentrations of 15d-PGJ2, 12-PGJ2, PGJ2, and PGD2 have been shown to activate this nuclear receptor [36
, 37
], it seems plausible that PPAR may represent another means for micromolar concentrations of PGD2 metabolites to inhibit the inflammatory response, although this has not been demonstrated directly. In contrast, a proinflammatory role for PPAR ligation by 15d-PGJ2 at much lower ligand concentrations has been observed recently in eosinophils [60
]. Picomolar concentrations of 15d-PGJ2 and the PPAR agonist, troglitazone, enhanced the in vitro CCL11-induced migration and actin polymerization in eosinophils [60
]. This response was inhibited by a PPAR antagonist, suggesting that the PPAR ligands were activating the eosinophils via the nuclear receptor [60
]. These results are difficult to reconcile with the published binding affinities of 15d-PGJ2 for PPAR, where micromolar concentrations were required to displace a radiolabeled PPAR ligand [36
, 37
], and in addition, previous studies show the PGs acting as PPAR ligands only at micromolar concentrations. The study, therefore, suggests that the relationship between the PGD2 metabolites and PPAR may not be as clear-cut as first thought.
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PGD2 ON MONOCYTES AND MACROPHAGES |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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Micromolar concentrations of 15d-PGJ2 and the PPAR agonist, troglitazone, have been shown to inhibit TNF-, IL-6, and IL-1ß production by activated monocytes [39
]. It appeared that 15d-PGJ2 was more efficient at reducing TNF- promoter activity than troglitazone, however, implying that the PG may be acting via PPAR-dependent and -independent mechanisms [39
]. A second group has investigated the effect of micromolar concentrations of 15d-PGJ2 on macrophage activation and found that 15d-PGJ2 and BRL 49653 inhibited the morphological changes associated with IFN- activation of the macrophages, and also reduced the expression of iNOS and subsequent NO production upon IFN- treatment [40
]. The inhibition of the expression of an iNOS promoter in a reporter assay was seen in PPAR-deficient RAW 264.7 cells, only after their transfection with the nuclear receptor, suggesting that the inhibition of iNOS expression is dependent on PPAR [40
]. A role for PPAR-independent signaling pathways in the response could not be ruled out, however, as the effects of the PG on endogenous iNOS expression was not assessed in the cells [40
]. Indeed, it has been proposed that 15d-PGJ2 does signal in RAW 264.7 cells by PPAR-independent mechanisms [39
], and in support of this, a later publication demonstrated that 15d-PGJ2 was able to inhibit NF-B signaling in the PPAR-deficient RAW 264.7 cells [48
].
Although having no effect on the viability of resting cells, 15d-PGJ2 potentiates the apoptosis of RAW 264.7 cells induced by LPS and IFN- via a p38 MAPK-dependent mechanism, which is thought to involve the production of ROS and reactive nitrogen species [62
]. In addition, although LPS alone does not affect RAW 264.7 viability, in conjunction with micromolar concentrations of 15d-PGJ2, apoptosis of the cells is induced [63
]. When the cells were stimulated with LPS and 15d-PGJ2 in the absence of IFN-, sufficient NO was not produced to form the pro-apoptotic ROS and reactive nitrogen species, and it was proposed that a mechanism involving prolonged PKC
activation was responsible for the cell death [63
]. The cyclopentenone PG, therefore, may inhibit the inflammatory response by aiding the clearance of activated macrophages [62
, 63
], in addition to reducing the cells’ expression of inflammatory cytokines and iNOS [39
, 40
].
PPAR is believed to exert its anti-inflammatory effects by the inhibition of several proinflammatory pathways, including STAT1, NF-B, and AP-1 signaling [40
]. As 15d-PGJ2 is known to inhibit NF-B independently of PPAR [47
, 48
], however, it is difficult to determine whether the effects observed in response to 15d-PGJ2 are PPAR-dependent or whether the PG is inhibiting NF-B independently of the receptor. Indeed, two recent papers studying PPAR-deficient murine embryonic stem cells have demonstrated that the inhibition of macrophage differentiation and cytokine expression by PPAR ligands is independent of the nuclear receptor [89
, 90
]. These groups did find, however, that the up-regulation of certain genes by PPAR ligands, such as the scavenger receptor CD36, is under the control of PPAR [89
, 90
], suggesting that although all the effects of 15d-PGJ2 on macrophages may not be PPAR-dependent, the PGD2 metabolites can impact the immune response by signaling via this receptor in monocytes and macrophages.
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PGD2 ON APCs |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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[64
].
In vivo, PGD2 produced by the helminth parasite, Schistosoma mansoni, has been shown to limit the immune response by inhibiting the migration of Langerhans cells from the skin to the draining lymph node [91
]. In contrast, in DP-deficient mice, APCs were able to migrate from the skin to the lymph node, and the worm burden was reduced, implying that DP mediates the inhibition of the APC migration by parasite-derived PGD2 [92
]. Similarly, PGD2, acting at DP, reduces DC migration from the lungs to the lymph node in a mouse model of antigen-driven lung inflammation [93
] and furthermore, limits T lymphocyte proliferation and cytokine generation in the lymph nodes of the PGD2-treated animals [93
]. DP signaling has been shown to have similar effects in a model of allergic skin inflammation with inhibition of Langerhans cell migration and T lymphocyte proliferation [64
]. In addition, in human skin explants, the TNF--induced migration of Langerhans cells is inhibited by activation of the PGD2/DP receptor axis [64
], demonstrating that the response seen in animal models is likely to be relevant in humans. Collectively, these data suggest that by its actions on DP, PGD2 acts to limit the immune response by inhibiting the APC migration to lymph nodes induced by a wide variety of stimuli.
Human monocytes and monocyte-derived DC express PPAR, and PGD2, via its metabolite 15d-PGJ2, may also limit APC activity by activating this nuclear receptor [65
]. At micromolar concentrations, PPAR agonists, including 15d-PGJ2, inhibit the LPS-induced maturation of DC [65
], and although this study does not demonstrate conclusively that the effects seen with these agonists are PPAR-dependent, it does suggest that at high concentrations, PGD2 metabolites have the ability to inhibit APC function [65
]. Indeed, 15d-PGJ2 was shown to reduce the ability of DC to stimulate T lymphocytes in a MLR, and the cyclopentenone PGs, 12-PGJ2 and 15d-PGJ2, inhibited the expression of the costimulatory molecules, CD80 and CD86, by monocyte-derived DC [94
].
Micromolar concentrations of PGD2 and its cyclopentenone metabolites, 15d-PGJ2 and 12-PGJ2, can also induce apoptosis of DC, and the cyclopentenone PG, PGA2, has also been reported to cause some cell death [94
]. A PPAR agonist had no effect on DC viability over the same time course; therefore, the induction of apoptosis was proposed to be independent of the receptor. The pan-caspase inhibitor, z-Val-Ala-Asp-fluoromethylketone, reduced the apoptosis to a degree, and it is interesting that it also inhibited the down-regulation of CD80 and CD86, implying that the induction of apoptosis and the inhibition of DC activity are mediated by caspase activation [94
]. The mechanism by which the cyclopentenone PGs activate the caspase cascade in DC is unclear, although it appears to be PPAR-independent, and as the cyclopentenone PG, PGA2, also caused cell death, it may be related to the reactive cyclopentenone ring [94
].
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PGD2 ON OTHER LEUKOCYTE TYPES |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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, although this has yet to be demonstrated definitively [95
]. 15d-PGJ2 also affects NK cells [96
]. The PG inhibits IFN- production and the cytolytic activity of these cells in PPAR-dependent and PPAR-independent manners [96
]. PGD2 and its metabolites, therefore, have far-reaching effects on many subsets of leukocytes. |
CONCLUSION |
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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The contrary effects of PGD2 are mirrored in the responses induced by its receptors (Table 1) . CRTH2 activates T lymphocytes, eosinophils, basophils, and monocytes [15 , 16 , 24 , 26 ] and in keeping with these findings, has been shown to be proinflammatory in vivo [5 , 23 , 33 , 34 ]. It is surprising, however, that increased eosinophilic inflammation was observed in CRTH2-deficent mice in a model of lung inflammation [32 ], suggesting that the receptor may have a previously unidentified anti-inflammatory role. The DP receptor, meanwhile, inhibits T lymphocyte, eosinophil, basophil, monocyte, and APC activation [15 , 16 , 24 , 59 , 64 ], implying an anti-inflammatory role; yet, in a model of antigen-induced airway inflammation, DP-deficient mice show markedly reduced inflammation, airway hyper-reactivity, and inflammatory cytokine production [20 ].
The situation is complicated further by the ability of the J series of PGD2 metabolites to signal independently of these cell surface receptors, for example, via PPAR ligation [36
, 37
] and NF-B inhibition [47
, 48
]. As these effects are thought to be mediated by micromolar concentrations of the J series of PGs, and the quantities in which the PGs are produced in vivo are believed to be much lower, their physiological relevance is often an issue of contention [97
]. In the study of Gilroy et al. [10
], only nanomolar concentrations of 15d-PGJ2 were detected in the plural exudate, for example, although it is important to note that locally produced levels may be far greater. Accurate measurement of the concentrations of PGs produced in vivo is difficult [97
, 98
], particularly the assessment of local concentrations; therefore, it is hard to draw conclusions about the physiological relevance of the effects of micromolar concentrations of the J series of PGs observed in vitro. The recent work using H-PGDS-deficient and overexpressing mice, however, strongly suggests that PGD2 or its metabolites are produced in quantities large enough to mediate NF-B inhibition in vivo [11
].
In summary, PGD2 and its metabolites have wide-ranging roles in leukocyte biology, acting via several different signaling mechanisms to play a pro- or anti-inflammatory role. The concentration of PG produced seems to be key to determining the outcome of PGD2 production, as is demonstrated in Table 1 . With some notable exceptions, the responses that occur at nanomolar concentrations would be expected to be pro-inflammatory, whereas those at micromolar concentrations are more likely to induce the resolution of the inflammation. Thus, PGD2 production in vivo may function by a see-saw mechanism—low levels of production acting to recruit and activate leukocytes [9 , 16 , 17 , 24 , 26 , 28 , 54 , 58 , 60 ] and greater concentrations to inhibit activation and induce apoptosis [15 , 39 , 40 , 43 , 55 , 61 , 62 , 63 , 64 , 96 ].
With important roles in the development and resolution of inflammation, PGD2 represents an attractive target for future therapies. Before such treatments progress further, however, it is important to consider the dual roles of this PG and its metabolites in the inflammatory response.
Received July 2, 2006; accepted September 12, 2006.
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TOPABSTRACTPGD2 AS A PRO-...PGD2 SIGNALINGPGD2 AND T LYMPHOCYTESPGD2 ON GRANULOCYTESPGD2 ON MONOCYTES AND...PGD2 ON APCsPGD2 ON OTHER LEUKOCYTE...CONCLUSIONREFERENCES |
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