12 The Korean Journal of Internal Medicine Vol. 26, No. 1, March 2011 that these two PGD2 receptors collaborate to regulate inflammatory cell functions by different mechanisms. Although many immune cells coexpress DP and CRTH2, CRTH2-mediated signals often predominate over DP- mediated signals when cells are exposed to the non-selec- tive agonist PGD2 [17,21,49], which binds to CRTH2 and DP with equal affinity [23,50]. One possible explanation for this observation may be the lower expression level of DP compared with that of CRTH2. Indeed, attempts to quantify DP and CRTH2 transcripts in immune cells, such as basophils, eosinophils, and TH2 cells, and in human air- way smooth muscle cells have revealed significantly lower DP expression [4,21,24,28,51,52]. Because both DP and CRTH2 expression levels can be upregulated and down- regulated by inflammatory stimuli [4,53,54], it is conceiv- able that the overall effect of PGD2 depends on the expres- sion level of PGD2 receptors in a given cell. Role of PGD2 in TH2 cell functions TH cells, particularly those of the TH2 cell-related inflammatory response, have a crucial role in asthma pathogenesis. The TH2 type response is coordinated by TH2 cell differentiation and a modification of TH2 cell functions, such as cytokine production, recruitment, pro- liferation, survival, and apoptosis. Differentiation into each TH cell subset is delicately controlled in vivo by inter- actions with DCs. Airway DCs [25-27] express both CRTH2 and DP. The role of CRTH2 in DC function remains unclear, whereas DP-mediated regulation of DCs has been demonstrated in several studies. PGD2 suppress- es the activation of DCs and prevents their migration into the T cell areas of draining lymph nodes [25]. This effect is mediated by DP. Indeed, it is mimicked by the DP-selec- tive agonist BW 245C, but not by the CRTH2-selective agonist DK-PGD2 [25]. This suppressive mechanism by DP may underlie the inhibition of TH2 cell differentiation. Furthermore, inhaling a selective DP agonist suppresses the cardinal features of asthma by targeting the functions of lung DCs [55]. Interestingly, an increase in Foxp3+ CD4+ regulatory T cells was observed in mice treated with a DP agonist or DP-agonist-treated DCs, which suppressed inflammation in an IL-10-dependent manner. In contrast, it has been proposed that the DP-mediated inhibition of the production of TH1-inducing cytokines, such as IL-12 [26], by DCs favors T-cell development towards the TH2 phenotype [27]. This effect has been observed in preclini- cal models, such as TH1-dependent delayed-type hyper- sensitivity reactions [56], although additional mecha- nisms involving PPAR activation have been proposed in some cases. Interestingly, DCs can themselves produce PGD2, which has been suggested to be involved in PGD2-mediated syn- thesis of CCL22/MDC, a chemoattractant for TH2 cells, in interferon (IFN)-γ-treated human keratinocytes [57]. DCs not only function as target of PGD2, but also may play an important role in modulating local immunity and inflam- mation though self-producing PGD2. Among human TH cell subsets, CRTH2 is preferentially expressed on TH2 cells, and is the most reliable marker to identify human CD4+ TH2 memory cells [32,58]. In con- trast, DP is expressed on both TH1 and TH2 cells. Importantly, CRTH2 mediates the migration of TH2 cells towards PGD2 [16] and delays TH2 cell apoptosis. Recently, human CRTH2+ TH2 memory cells were reported to be main- tained by TSLP-activated DC. Furthermore, CRTH2+CD4+ TH2 memory cells activated by TSLP-DCs undergo further TH2 polarization and express prostaglandin PGD2 syn- thase. Thus, in cooperation with DC-derived PGD2, TH2 cell-derived PGD2 may promote further accumulation of TH2 cells to the inflamed tissue [59] by positive feedback mechanisms, causing persistent inflammation and dam- age to the asthma airways. Another notable role of PGD2 is regulating the produc- tion of proinflammatory cytokines in TH2 cells [28,51]. Tanaka et al. have shown that human CD4+ and CD8+ T cells producing IFN-γ and IL-2 are reduced in number by DP-mediated signals [28], whereas CRTH2-mediated sig- nals enhance the ability of human TH2 cells to produce IL- 2, IL-4, IL-5, and IL-13, an effect that was inhibited by ramatroban [51]. This PGD2-mediated effect on cytokine production by TH2 cells is mimicked by the selective CRTH2 agonist DK-PGD2 [51]. CRTH2-mediated PGD2 effects were dominantly observed on CRTH2+ TH2 cells, compared with DP-mediated effects after treatment with BW 245C, resulting in the attenuated production of cytokines by TH2 cells [28]. Furthermore, activation of TH2 cells in response to supernatants from immunologi- cally activated human mast cells is mediated by PGD2, through an action on CRTH2 [60]. Together, these find- ings suggest that PGD2 favors TH2 functions through CRTH2 for recruiting TH2 cells to sites of allergic inflam- mation and for driving TH2-cytokine production, while restraining TH1 functions via DP, which may contribute to the development of TH2-dominated status during allergic inflammation. However, CRTH2 expression in mice is not