title: Opposing immunomodulatory roles of prostaglandin D2 during the progression of skin inflammation.
abstract: The effects of PGD2 are extremely context dependent. It can have pro- or anti-inflammatory effects in clinically important pathological conditions. A greater mechanistic insight into the determinants of PGD2 activity during inflammation is thus required. In this study, we investigated the role of PGD2 in croton oil-induced dermatitis using transgenic (TG) mice overexpressing hematopoietic PGD synthase. Administration of croton oil caused tissue swelling and vascular leakage in the mouse ear. Compared with wild-type animals, TG mice produced more PGD2 and showed decreased inflammation in the early phase, but more severe manifestations during the late phase. Data obtained from bone marrow transplantation between wild-type and TG mice indicated that PGD2 produced by tissue resident cells in the TG mice attenuated early-phase inflammation, whereas PGD2 produced from hematopoietic lineage cells exacerbated late-phase inflammation. There are two distinct PGD2 receptors: D-prostanoid receptor (DP) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). In TG mice, treatment with a DP antagonist exacerbated inflammation in the early phase, whereas treatment with a CRTH2 antagonist attenuated inflammation during the late phase. In vitro experiments showed that DP agonism enhanced vascular endothelial barrier formation, whereas CRTH2 agonism stimulated neutrophil migration. Collectively, these results show that when hematopoietic PGD synthase is overexpressed, tissue resident cell-derived PGD2 suppresses skin inflammation via DP in the early phase, but hematopoietic lineage cell-derived PGD2 stimulates CRTH2 and promotes inflammation during the late phase. DP-mediated vascular barrier enhancement or CRTH2-mediated neutrophil activation may be responsible for these effects. Thus, PGD2 represents opposite roles in inflammation, depending on the disease phase in vivo.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan;
authors.forename: Hana
authors.initials: H
authors.lastname: Sarashina
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsubosaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Omori
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D003872:Dermatitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D007155:Immunologic Factors / Q000378:metabolism* / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D015230:Prostaglandin D2 / Q000378:metabolism* / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007155:Immunologic Factors; D054834:Lipocalins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor