osed as selective markers of mast cell activation in vivo. Cross linking of cell surface immunoglobulin E by allergen leads to the rapid production of PGD2 by mast cells. PGD2 is derived from liberated arachidonic acid in a two-step process where either COX1 or COX2 catalyses the production of PGH2, which is then metabolized to PGD2 by haematopoietic PGD2 synthase. Using mouse mast cells in vitro, it has been shown that the early phase of PGD2 production is COX1-dependent whereas COX2 is responsible for the more prolonged production of PGD2. In vivo, it appears that PGD2 is produced more rapidly which may reflect the presence of COX2 in these chronically inflamed tissues as has been shown in the buy 481-53-8 airways of aspirinintolerant asthmatics. Allergen challenge has been shown to lead to rapid production of PGD2 in the airways of asthmatics, the nasal mucosa of allergic rhinitis and in the skin of patients with atopic dermatitis. PGD2 is also produced in biological meaningful quantities by Th2 cells although the levels are around 1/10th of those produced by mast cells on a per cell basis and is more delayed. In response to anti-CD3/anti-CD28, PGD2 is produced by human Th2 cells as a consequence of induction of COX2 and haematopoietic PGD2 synthase. Whether dendritic cells produce PGD2 is more controversial but interestingly, dendritic cells incubated with thymic stromal lymphopoietin create a local environment where Th0 cells polarize to the Th2 phenotype and this process is associated with the upregulation of PGD2 synthase in Th2 cells. It is likely therefore that Th2 cells may be an important source of biologically active PGD2 in a chronic allergic setting or in situations where the allergic response occurs independently of mast cell activation. Pharmacological properties of DP1 and CRTH2 D prostanoid receptor 1 was the first receptor that was identified for PGD2. DP1 is a member of the prostanoid receptor family that includes EP14, FP, IP and TP. It is coupled to Gas and its activation leads to elevation of British Journal of Pharmacology 153 S191S199 intracellular levels of cAMP. DP1 is expressed by vascular smooth muscle and platelets and has well-characterized effects in mediating vasodilatation and inhibition of platelet aggregation. Much of our knowledge of the role of DP1 in biological responses PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19803812 comes from the use of the selective DP1 agonist BW245C and the selective DP1 antagonist BWA868C. Dendritic cells express DP1 and activation of DP1 may play an important role in modulating the function of these cells, particularly in controlling the production of cytokines such as interleukin 12. Chemoattractant receptor-homologous molecule expressed on Th2 cells was originally identified as an orphan known as GPR44. Subsequently, it was found that CRTH2 is expressed preferentially by Th2 lymphocytes, eosinophils and basophils 
and it mediated chemotactic responses of Th2 lymphocytes, eosinophils and basophils to PGD2. Although CRTH2 and DP1 bind the same ligand there is very little homology between the two receptors, CRTH2 being most closely related to other chemotactic receptors such as the leukotriene B4 receptors BLT1 and BLT2, the complement C5a receptor and the formyl peptide receptors. CRTH2 is coupled to Gai and its activation leads to elevation of intracellular calcium and reduction in cAMP. Downstream activation of CRTH2 results in phosphatidylinositol-3-kinase -dependent phosphorylation of AKT, phosphorylation of GSK-3b and nuclear tra
