title: Prostaglandin E2-prostaglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression.
abstract: UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4(+)/forkhead box P3-positive (Foxp3(+)) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-κB ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E(2) (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis.
authors: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan.
authors: Kitipong
authors: K
authors: Soontrapa
authors: Tetsuya
authors: T
authors: Honda
authors: Daiji
authors: D
authors: Sakata
authors: Chengcan
authors: C
authors: Yao
authors: Takako
authors: T
authors: Hirata
authors: Shohei
authors: S
authors: Hori
authors: Toshiyuki
authors: T
authors: Matsuoka
authors: Yoshihiro
authors: Y
authors: Kita
authors: Takao
authors: T
authors: Shimizu
authors: Kenji
authors: K
authors: Kabashima
authors: Shuh
authors: S
authors: Narumiya
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000528:radiation effects*; D007213:Indomethacin / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C545651:Ptger4 protein, mouse; D053245:RANK Ligand; D058309:Receptors, Prostaglandin E, EP4 Subtype; C505689:Tnfsf11 protein, mouse; D015232:Dinoprostone; D007213:Indomethacin