tributes to eosinophilic inflammation, a prominent patho- logical feature in most asthma. TH2 cytokines also trigger the production of chemokines, including CCL11/eotaxin, CCL17/TARC, and CCL22/macrophage-derived chemokine (MDC), in tissue fibroblasts or epithelial cells, promoting the infiltration of inflammatory cells, such as eosinophils and TH2 cells into sites exposed to allergens. Importantly, IL-4 and IL-13 stimulate immunoglobulin class switching, leading to IgE production, which binds to its high-affinity receptor (FcεRI) on the surface of mast cells or basophils. The association of captured allergens with IgE bound to FcεRI on the cell surface activates sig- nal transduction in these cells and rapidly leads to the release of inflammatory cytokines and chemical media- tors, such as histamine and leukotrienes in mast cells and basophils and PGD2 in mast cells. Furthermore, particular interest has been generated in novel epithelial cell-derived cytokines including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33, which have all been implicated in promoting TH2 cytokine responses, and their ability to influence innate and adaptive immune responses associat- ed with TH2 cytokine-mediated inflammation in airways. Recent evidence suggests that coordinated expression and cross-regulation between TSLP, IL-25, and IL-33 are cru- cial events for developing TH2 cell-mediated airway immune responses in asthma. In contrast, PGD2 modu- lates airway physiology by causing bronchoconstriction, vasodilation, increases in capillary permeability, and mucous production in asthma. These functions are well- known effects that may facilitate transendothelial migra- tion of inflammatory cells, such as eosinophils, mast cells, lymphocytes, and monocytes, during allergic inflamma- tion. In addition to such classical effects, novel properties of PGD2 include TH2 inflammation in allergic diseases (Fig. 1). PGD2 and its metabolites PG production begins with the liberation of arachidonic acid from membrane phospholipids by phospholipase A2 in response to inflammatory stimuli. Arachidonic acid is converted to PGH2 by the cyclooxygenase enzymes COX-1 and COX-2. PGH2 is a common precursor of several PGs, including PGD2, which is generated by the actions of two PG synthases, known as the lipocalin-type PGD synthase (L-PGDS), primarily expressed in brain, heart, and adi- pose tissue, and the hematopoietic PGD synthase (H- PGDS), mainly expressed in mast cells, macrophages, Arima M and Fukuda T. Role of prostaglandin D2 in asthma 9 dendritic cells (DCs), and TH2 cells. It is generally thought that COX-1 is expressed constitutively in most tissues of the body and functions to maintain homeostatic process- es, such as mucus secretion. In contrast, COX-2 is primar- ily an inducible enzyme, involved mainly in the regulation of inflammation [3]. PGD2 is a major product from COX- catalyzed reactions in a variety of tissues and cells, includ- ing those of the immune system, such as T cells, DCs, macrophages, mast cells, and platelets. PGD2 production in asthma Fujitani et al. [4] generated transgenic mice overex- pressing lipocalin-like PGD synthetase in the lung and subjected them to ovalbumin (OVA)-induced pulmonary allergic inflammation. They found elevated IL-4 and IL-5 concentrations and increased eosinophilic infiltration in bronchoalveolar-lavage fluid (BALF) in these mice. Mandal et al. [5] reported that a reduction in PGD2 syn- thesis, induced by uteroglobin, an anti-inflammatory pro- tein, was associated with reduced allergic inflammation. Furthermore, PGD2 nebulization before aerosol Ag chal- lenge enhanced TH2 inflammatory responses, including eosinophilia, and leads to the development of AHR [6]. Collectively, these findings appear to substantiate the pro- posal that PGD2 acts as an important mediator in allergic asthma. Activated mast cells contribute to asthmatic pulmonary inflammation by producing a variety of chemical media- tors and cytokines. During allergic responses, PGD2 is released in large amounts by mast cells during asthmatic attacks in humans. DCs [7] and TH2 cells [8] also produce PGD2. Furthermore, fibroblasts, bronchial smooth muscle cells, and airway epithelial cells are also thought to pro- duce PGD2, precipitating pulmonary inflammation. It is well established that the presence of an allergen triggers PGD2 production in sensitized individuals. In individuals with asthma, a bronchial allergen challenge leads to rapid PGD2 production, which can be detected in the BALF within minutes, reaching biologically active levels at least 150-fold higher than pre-allergen levels [9]. A local anti- gen challenge also stimulates PGD2 production in the nasal mucosa of patients with allergic rhinitis [10] and in the skin of patients with atopic dermatitis (AD) [11]. Several lines of evidence support the view that mast cells are the principal sources of PGD2 at allergic inflammation sites. Cell fractionation studies have shown that PGD2 is produced predominantly by mast cells [12], and mast cell