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Antagonism of the Prostaglandin D Receptors DP and CRTH2 As An REVIEWS Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases Roy Pettipher*, Trevor T. Hansel‡ and Richard Armer* Abstract | Immunological activation of mast cells is an important trigger in the cascade of inflammatory events leading to the manifestation of allergic diseases. Pharmacological studies using the recently discovered DP1 and CRTH2 antagonists combined with genetic analysis support the view that these receptors have a pivotal role in mediating aspects of allergic diseases that are resistant to current therapy. This Review focuses on the emerging roles that DP1 and CRTH2 (also known as DP2) have in acute and chronic aspects of allergic diseases and proposes that, rather than having opposing actions, these receptors have complementary roles in the initiation and maintenance of the allergy state. We also discuss recent progress in the discovery and development of selective antagonists of these receptors. Prostaglandin Prostaglandins D2 (PGD2) is an acidic lipid mediator that leads to the rapid production of PGD2, which can be Acidic lipids derived from the is derived from arachidonic acid by the sequential action detected in the bronchoalveolar lavage fluid within metabolism of arachidonic acid of cyclooxygenase(s) (COX) and PGD2 synthase(s). The minutes, reaching biologically active levels at least by the action of cyclo- COX(s) convert arachidonic acid in a two-step process 150-fold higher than pre-allergen levels10. Local anti- oxygenase enzymes and to first PGG and then PGH . These unstable endoper- gen challenge also stimulates PGD production in the downstream synthase 2 2 2 11 enzymes. Prostaglandins have oxide intermediates are converted to PGD2 by either the nasal mucosa of patients with allergic rhinitis and in (FIG. 1) 12 a diverse range of activities and haematopoietic or lipocalin PGD2 synthase . PGD2 the skin of patients with atopic dermatitis . Several have a well recognized role in is produced in the brain where it might be involved in lines of evidence support the view that mast cells pain and inflammation. 1 the regulation of sleep and other central nervous system are the principal sources of PGD2 at sites of allergic Prostaglandin D2 (PGD2) is the 2 main prostanoid produced by (CNS) activities, which includes pain perception . In inflammation. Cell fractionation studies have shown 13 mast cells and is the peripheral tissues, the richest cellular source of PGD2 is that PGD2 is produced predominantly by mast cells , predominant prostaglandin mast cell the — PGD2 is produced by immunoglobulin and, in chopped human lung parenchyma, mast-cell found at sites of allergic 14 E (IgE)-activated mast cells at levels of around 50 ng per activation is a requirement for PGD2 generation . Also, inflammation. 1 × 106 cells3,4. Other leukocyte populations, such as den- although both mast cells and basophils produce hista- dritic cells5 6 and T helper 2 (TH2) cells , also produce PGD2, mine, basophils do not produce appreciable quantities (REF. 7) but at levels far lower than those produced by mast cells. of PGD2 . This is relevant when discerning the Although non-mast-cell sources of PGD2 might have principal cellular source of PGD2, as PGD2 is produced important functions in some settings, such as in dendritic during the early response to allergen only, unlike his- cell and TH2 lymphocyte interactions, measurement of tamine, which is produced during the early and late *Oxagen Limited, 91 Milton 15 PGD2 and its metabolites has been proposed as selective phases . These data are therefore consistent with the Park, Abingdon, Oxfordshire markers of mast-cell activation in clinical asthma7–9. The view that mast cells are responsible for the bulk of PGD OX14 4RY, UK. 2 G-protein-coupled receptors (GPCRs) — CRTH2 (also production in an allergic setting. However, PGD that ‡National Heart and Lung 2 DP TP Institute Clinical Studies Unit, known as DP2), 1 and — that have an important role is produced by mast cells might provide an essential Royal Brompton Hospital, in mediating the biological effects of PGD2 are detailed in link between the early phase and the late-phase aller- Fulham Road, BOX 1, and the known natural and synthetic ligands for gic response by initiating cellular processes that lead to London SW3 6HP, UK. these receptors are detailed in TABLE 1. the recruitment and activation of T 2 lymphocytes and Correspondence to R.P. H eosinophils e-mail: It is well established that the presence of an allergen with associated pathophysiological effects. [email protected] triggers the production of PGD2 in sensitized indi- The mechanisms by which mast-cell-derived PGD2 doi:10.1038/nrd2266 viduals. In asthmatics, a bronchial allergen challenge orchestrates these effects are the focus of this Review. NATURE REVIEWS | DRUG DISCOVERY VOLUME 6 | APRIL 2007 | 313 © 2007 Nature Publishing Group REVIEWS Phospholipases The diverse activities of PGD2 in the control of local Phospholipids Arachidonic acid + lysophospholipids blood flow, bronchial airway calibre and leukocyte function are mediated by high affinity interactions Cyclooxygenases Precursor with the GPCRs CRTH2, DP1 and TP. In addition to Biologically active the effects that are mediated by the GPCRs discussed in PGG2 PGI2 12 Major metabolite this Review, PGD2 can be metabolized to Δ PGJ2 and 15-deoxy-Δ12,13PGJ , which have effects relevant to the Secondary metabolite 2 resolution of inflammation, including the inhibition of cytokine production and the induction of apoptosis. These effects are mediated by intracellular actions that Thromboxane A2 PGH2 PGE2 are mediated by both peroxisome proliferator-activated γ γ 22 γ PGD2 synthases receptor- (PPAR )-dependent and PPAR -independ- Isomerization ent mechanisms, the latter of which involves the inhibi- with albumin 11-ketoreductase κ κ 23 Δ12 α β tion of nuclear factor- B (NF B) activation . Generally, PGD2 PGD 9 11 PGF2 2 concentrations of ligand in the micromolar range have been used to observe the intracellular effects of these –H2O 15 PG dehydrogenase PGD metabolites. As these observations are of phar- –H2O 2 macological interest, the physiological significance of these findings has been questioned because of the high PGJ 2 concentrations that are needed to induce these effects relative to the concentrations of the PGD2 metabolites Δ12,14 Isomerization –H2O 24 15-deoxy- PGD2 with albumin 13,14-dihydro-15-keto-PGD2 that are likely to be formed in vivo . Effects of PGD2 relevant to allergic diseases Δ12 Δ12,14 PGJ2 15-deoxy- PGJ2 Having established that mast-cell-derived PGD2 is pro- duced in high concentrations in response to an allergen Figure 1 | Pathways of PGD metabolism. On cellular activation arachidonic acid is 2 challenge, it is interesting to note that PGD can mimic released from membrane phospholipids and converted to the cyclic endoperoxide 2 prostaglandin G (PGG ) by the action of cyclooxygenase 1 (COX1) or COX2. The a number of key features of allergic diseases. Studies in 2 2 preclinical species have observed the following features peroxidase activity of the same enzymes leads to the formation of PGH2, which can be converted to a number of biologically active prostaglandins by discrete synthase when PGD2 is applied to in vivo preparations, or its over- enzymes that show tissue-specific distribution and might demonstrate preferential production is engineered by genetic manipulation: coupling to either COX1 or COX2. PGD2 production is dependent on the action of either • Vasodilatation leading to erythema (flare) and the lipocalin PGD2 synthase or the haematopoietic PGD2 synthase. Haematopoietic PGD2 potentiation of oedema (wheal). synthase is present in mast cells, T helper 2 (T 2) cells and other leukocytes, and it is H • Recruitment of eosinophils and T 2 lymphocytes. thought to be responsible for the bulk of PGD production during allergic responses. H 2 • Modulation of T 2-cytokine production. PGD is rapidly metabolized (with a half-life of 1.5 min in blood), and the main products H 2 • Bronchoconstriction. that have been detected in vivo are Δ12PGJ and 9α11βPGF The precise pathway of PGD 2 2. 2 The capacity of PGD to cause or potentiate inflam- metabolism has not been fully elucidated but it is possible that 13,14-dihydro-15-keto- 2 Δ12 Δ12,14 matory responses has been appreciated for a long time. PGD2 (DK-PDG2), PGD2 and 15-deoxy- PGJ2 might be formed locally, which is of Δ12 Injection of PGD into human skin has been shown to interest as these compounds, similar to PGJ2, retain significant chemoattractant 2 produce a long lasting erythema25,26, to potentiate the receptor-homologous molecule expressed on TH2 cells (CRTH2)-agonist activity. effects of other mediators on induration and leukocyte infiltration in human skin26 and to enhance oedema for- 25 PGD2 metabolism mation in rat skin . It is most likely that these effects of The proposed pathways of PGD2 metabolism are shown PGD2, like those of other vasodilator prostaglandins, are in FIG. 1. It is of particular interest that a number of due to an increased blood flow to the inflamed lesion27 and Mast cell A granular cell that bears Fc known and putative PGD2 metabolites such as 13,14- are, therefore, most likely to be mediated predominantly 16 Δ12 (REF. 17) receptors for immunoglobulin E dihydro-15-keto-PGD2 (DK-PGD2) , PGD2 , by the DP1 receptor. This is based on studies showing that (IgE), which, when crosslinked Δ12 (REF. 18) Δ12,14 (REF. 19) PGJ2 , 15-deoxy- PGD2 , 15-deoxy- the DP1 agonist BW245C relaxes vascular smooth muscle by IgE and antigen, causes Δ12,14PGJ (REF. 19) and 9α11βPGF (REF. 20)retain activity preparations and the selective DP antagonist BWA868C degranulation and release of 2 2 1 (REF. 28) mediators such as histamine, on CRTH2, but are less active on DP1. This implies that blocks the vasodilator effect of PGD2 .
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