asthma in a murine model by down-modulating lung DC function and inducing regulatory T cells. In contrast, DP is expressed by epithelial cells, fibroblast cells, and certain leukocyte populations [25-28] including monocytes, DCs, T cells, basophils, eosinophils, and mast cells, where it has been suggested to control several functions including the production of cytokines and lipid mediators. PGD2 syner- gizes with tumor necrosis factor via DP receptors to pro- mote CCL2/MCP-1 and IL-8 production in monocytic cells [29]. urthermore, Matsuoka et al. [30] examined the role of DP in asthma by studying DP receptor-deficient mice in a model of OVA-induced allergic inflammation. Loss of DP did not affect the primary immune response, because similar serum total and OVA-specific IgE concen- trations were observed in immunized wild-type and DP- deficient mice. However, the concentrations of TH2 cytokines, such as IL-4, IL-5, and IL-13, were significantly reduced, and lymphocyte and eosinophil accumulations in BALF were significantly suppressed in DP-deficient mice, compared with wild-type mice after the OVA challenge. While extensive cell infiltration and occasional bronchus- associated lymphoid tissue formation were consistently found in the lungs of all OVA-challenged wild-type mice, minimal cell infiltration was detected in the lungs of OVA- challenged DP-deficient mice. In contrast to wild-type mice, few mucus-containing cells were detected in the air- ways of DP-deficient mice. Moreover, whereas the OVA challenge significantly increased airway sensitivity to acetylcholine in wild-type mice, a minimal increase was detected in DP-deficient mice. Thus, PGD2 appears to act on DP and play an important role eliciting certain key fea- tures of allergic asthma. This has been confirmed by other experiments. Arimura et al. [31] administered the DP antagonist S-5751 orally to a similar guinea pig model of OVA-induced allergic asthma and found that it signifi- cantly alleviated eosinophil infiltration into the lung. Moreover, an association of DP promoter and gene poly- morphisms with asthma has been detected in humans [32]. Thus, a DP-mediated PGD2 effect is expected to be involved in allergic and/or asthmatic responses. CRTH2 was originally identified as an orphan receptor, expressed on type 2 polarized lymphocytes (TH2 and Tc2) [33], basophils, eosinophils [34], and monocytes [35], and mediates its effects by promoting the activation and chemotaxis of TH2 cells, eosinophils, basophils [16], and monocytes [35]. Despite binding to PGD2 with a similar affinity to DP, CRTH2 is not structurally related to DP and signals through a different mechanism. The effects of Arima M and Fukuda T. Role of prostaglandin D2 in asthma 11 CRTH2 are mediated through a Gαi-dependent increase in intracellular calcium levels and a reduction in intracel- lular cAMP levels, indicating that CRTH2-mediated sig- nals are predominantly proinflammatory. Unlike the prostanoid DP receptor, CRTH2 is a member of the chemoattractant receptor family, sharing higher sequence homology to the fMLP and C5a receptors than to the prostanoid receptor family [16]. The PGD2 metabolites, 13, 14-dihydro-15-keto PGD2 (DK-PGD2), ∆12 PGD2, PGJ2, ∆12- PGJ2, 15d-PGJ2, and 9α, 11β-PGF2 bind to CRTH2 [16,17,36] and activate eosinophils [36-38]. PGF2α is a stereoisomer of 9α, 11β-PGF2, produced from PGH2 by the action of PGF synthase and from PGE2 by the action of PGE9-ketoreductase, independently of PGD synthetase. PGF2 is also implicated in CRTH2 signaling in the pres- ence or absence of PGD2 production [39]. CRTH2 can also be activated by the thromboxane A2 metabolite, 11-dehy- dro-TBX2 [40]. The existence of these CRTH2 agonists suggests that this receptor may be of physiological impor- tance even in the absence of basal PGD2 production. Ramatroban (BAYu3405) is an effective CRTH2 antago- nist [41]. Ramatroban was originally identified as a TP antagonist, but it has been discovered that this drug binds to the CRTH2 receptor with moderate affinity (its antago- nistic activity against CRTH2 is about 10-fold lower than that against TP) and blocks responses to the selective CRTH2 agonist DK-PGD2, in vitro and in vivo [41,42]. Uller et al. [43] studied the specificity of CRTH2 antago- nism by TM30089, which is closely related structurally to dual TP/CRTH2 antagonists in mice. They assessed the inhibition of asthma-like pathological characteristics. Studies with these antagonists suggest that CRTH2 plays an important role mediating airway inflammation in response to an allergic challenge in both the guinea pig nasal mucosa [44] and mouse airway [45]. In humans, CRTH2 activation is responsible, at least in part, for the implications of PGD2 in asthma and inflammatory dis- eases [46,47] as well as allergic rhinitis [48] Thus, CRTH2 is considered to play an important role in allergic inflam- mation, similar to DP. PGD2 enhances or suppresses inflammation by acting on different receptors expressed by hematopoietic and non-hematopoietic cells. Several cells of the immune sys- tem express both DP and CRTH2, which are coupled to apparently opposing signaling pathways. Because DP acti- vation is often associated with inhibition of immune cell function [20], whereas CRTH2 activation leads to immune cell activation [20], it is tempting to hypothesize