degranulation [21,22,38,39], whereas DP activation is linked to eosinophil apoptosis [21], hich is delayed by BW 245C but not DK-PGD2. However, inhibiting DP with the selective antagonist BW A868C resulted in markedly enhanced CRTH2-mediated activation, as assessed by an increase in CD11b expression on exposure to PGD2 [22]. Novel effects of PGD2 on eosinophils have been reported by Mesquita-Santos et al. [67]. They showed that adminis- tering PGD2 to mice enhanced leukotrienes (LT) C4 pro- duction by inducing lipid body-driven LTC4 synthesis, dependant on the synergistic activity of endogenous eotaxin, acting via the CCR3 receptor. Opposing effects of DP and CRTH2 on cell function have also been observed in basophils, circulating leuko- cytes that are particularly relevant during the late phase of the allergic response and for asthmatic inflammation [24]. CRTH2 signaling is responsible for mobilizing intracellu- lar Ca2+ in basophils, upregulating CD11b and CD203c expression, and enhancing IgE-mediated basophil degranulation [68]. Conversely, DP activation inhibits basophil migration and IgE-mediated degranulation. Thus, it seems that activating basophils and eosinophils, balanced by PGD2 via the dual receptor system, plays an important role in asthma. According to CRTH2 and DP studies, these two receptor subtypes may collaborate in the activation and accumula- tion of inflammatory cells, such as mast cells, eosinophils, and basophils, at sites of allergic inflammation (Fig. 2). Role of the PGD2 receptor in allergic disease patho- genesis Recent studies have shown an accumulation of CRTH2- positive leukocytes, including TH2 cells, eosinophils, basophils, and mast cells, in human allergic inflammatory regions. Furthermore, CRTH2 mRNA and protein levels are higher in eosinophils from atopic subjects than in those from healthy controls [69]. Consistent with the increased number of CRTH2 receptors in eosinophils from atopic individuals, PGD2-induced chemotaxis is sig- nificantly higher in these cells. Increased levels of CRTH2 expression and an enhanced sensitivity of eosinophils to PGD2 might explain the tissue eosinophilia in atopic patients. Furthermore, the percentage of CD4+ T cells expressing CRTH2 in patients with AD correlates with dis- ease severity [70-72]. Additionally, available evidence indicates that genetic alterations in CRTH2 are related to allergic asthma. Genetic variants of CRTH2 predispose Arima M and Fukuda T. Role of prostaglandin D2 in asthma 15 individuals to develop asthma. CRTH2 is associated with severe asthma in African-American and Chinese popula- tions [70]. Associated polymorphisms in the 3’-untrans- lated region of CRTH2 lead to increased mRNA stability, suggesting that CRTH2 variants are associated with high- er degrees of bronchial hyperresponsiveness and are causally linked to asthma [70]. These findings indicate that higher CRTH2 expression levels and increased responsiveness to its PGD2 ligand may be the biological basis for the association of this receptor with asthma. In contrast, variants of PTGDR (the gene encoding DP1) with reduced transcriptional activity have been detected in patients with asthma [73]. Studies in a small cohort of patients with asthma provided evidence that these puta- tive loss-of-function variants protect against asthma development. CONCLUSION PGD2 has been recognized as an important mediator of allergic responses. It is becoming clear that PGD2 and its metabolites may play important roles in the pathogenesis of allergic diseases, including asthma. Although the poten- tial clinical benefits of modifying PGD2-related receptor function remain unsubstantiated, many studies have pro- vided promising evidence that these receptors are immune and inflammatory regulators in various immune cells. The roles of DP and CRTH2 are diverse and complex in the allergic system. Thus, future studies into the func- tion (s) of these receptors will likely lead to new approach- es for the treatment and, perhaps, prevention of allergic diseases, including asthma. Conflict of interest No potential conflict of interest relevant to this article was reported. Acknowledgements We thank Emiko Ohta for help in preparing the manu- script.