14 The Korean Journal of Internal Medicine Vol. 26, No. 1, March 2011 and type II alveolar epithelial cells. Moderate expression was also found in type I alveolar epithelial cells and inflammatory white blood cells [30]. Airway epithelium has been proposed to be a source of proinflammatory cytokines and chemokines during asthma pathogenesis [64]. These findings suggest the following model for PGD2 in asthma: mast cell-derived PGD2 acts at DP receptors in the epithelium and stimulates the production and release of cytokines and chemokines to induce airway inflamma- tion, obstruction, and hyper-reactivity. Chiba et al. report- ed that PGD2 induced IL-8 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells in association with mitogen-activated protein (MAP)/ERK and p38 MAP kinase activation via a CRTH2-independent pathway [65]. To further investigate the involvement of bronchial epithelial cells, Honda et al. [6] established a novel experimental model of asthma that permitted the direct assessment of the role of PGD2 in airway inflamma- tion. Antigen-sensitized mice were exposed to aerosolized PGD2 1 day before challenge with low-dose aerosolized antigen. The results showed that not only the numbers of eosinophils, lymphocytes, and macrophages, but also the levels of IL-4 and IL-5 in BALF were higher in PGD2-pre- treated mice than in control mice. Moreover, the expres- sion of MDC, a TH2 cell chemoattractant, was higher in PGD2-pretreated mice than in controls. Furthermore, the authors showed that injecting anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as TH2 cytokine production after antigen challenge. These results indicate that PGD2 accel- erates TH2 type inflammation by inducing MDC. However, unfortunately, the PGD2 receptor required for the epithe- lial induction of MDC expression has yet to be identified, although DP is a candidate receptor for the initiation of MDC production in epithelial cells. Recently, a novel aspect of DP in airway epithelial cells was shown by Mandal et al. [5]. They demonstrated that uteroglobin (UG)-deficient mice had elevated levels of PGD2 in BALF and increased COX-2 gene expression in epithelial cells. They also found that DP signaling was mediated via p38 MAP kinase (MAPK), p44/42 MAPK, and protein kinase C (PKC) pathways in a cell type-specif- ic manner, leading to the activation of nuclear factor (NF)- KB, which then stimulated COX-2 expression.UG as also found to bind PGD2, block DP signaling, inhibit NF-KB activation, and, consequently, suppress COX-2 gene expression. These studies demonstrated that DP signaling mediated allergic inflammatory responses by activating NF-KB, which stimulated COX-2 expression. This phe- nomenon is also observed in fibroblasts and smooth mus- cle cells. Thus, in asthma, DP augments the production of COX-2 metabolites of arachidonic acid, including PGD2, in airway epithelial cells by an autocrine mechanism, result- ing in their local accumulation and further production of chemokines. UG thus appears to be a key component of an innate homeostatic mechanism, acting to prevent stim- ulation of an allergen-induced, DP-mediated inflammato- ry response (Fig. 2). Role of PGD2 in inflammatory cell functions (mast cells, eosinophils, and basophils) TH2 cells play an important role in allergic disease by organizing the characteristic inflammatory response, involving mast cells, basophils, and eosinophils. These inflammatory cells also produce TH2 type cytokines, indi- cating that these cells and TH2 cells interact to promote TH2 type inflammation in asthma. While the above studies suggest an important role for PGD2 in asthma pathogene- sis, DP suppresses mast cell activation. Chan et al. [66] collected rat peritoneal mast cells and examined the effects on anti-IgE-induced histamine release of agonists specific to various types of prostanoid receptors. They found that several prostanoid agonists inhibited histamine release; BW 245C and ZK 118182 were the most potent. Based on these findings, they suggested that developing highly specific agonists for the mast cell DP receptor might improve the management of allergic diseases, such as asthma. In contrast, Matsuoka et al. [30] showed that the net action of DP in allergic asthma appears to be facili- tative, given that DP is present. Strong evidence support- ing a role for CRTH2 in mast cells is lacking, although the receptor is expressed. In contrast, activating CRTH2 induces migration of murine mast cells, based on the upregulation of CD23 and CD30 on the cell surface. Eosinophils express both DP and CRTH2, which inter- act to regulate cellular responses to PGD2. Previous stud- ies have revealed that CRTH2 mediates eosinophil chemo- taxis induced by mast cell products [34]. The receptor directly responsible for stimulating eosinophil migration appears to be CRTH2, not DP [16]. Gervais et al. [21] found that DK PGD2, a CRTH2 agonist, stimulated chemokinesis and degranulation of eosinophils, whereas BW 245C did not. CRTH2 activation also leads to changes in the shape of eosinophils, chemotaxis, enhanced chemo- tactic responsiveness to other chemoattractants, and