title: Dual functions of prostaglandin D2 in murine contact hypersensitivity via DP and CRTH2.
abstract: Prostaglandin D2 (PGD2) exerts its effects through two distinct receptors: the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the D prostanoid (DP) receptor. Our previous study demonstrated that CRTH2 mediates contact hypersensitivity (CHS) in mice. However, the function of DP receptor remains to be fully established. In this study, we examine the pathophysiological roles of PGD2 using DP-deficient (DP(-/-)) and CRTH2/DP-deficient (CRTH2(-/-)/DP(-/-)) mice to elucidate receptor-mediated PGD2 action in CHS. We observed profound exacerbation of CHS in DP(-/-) mice. CRTH2(-/-)/DP(-/-) mice showed similar exacerbation, but to a lesser extent. These symptoms were accompanied by increased production of interferon-γ and IL-17. The increase in IL-17 producing γδ T cells was marked and presumably contributed to the enhanced CHS. DP deficiency promoted the in vivo migration of dendritic cells to regional lymph nodes. A DP agonist added to DCs in vitro was able to inhibit production of IL-12 and IL-1β. Interestingly, production of IL-10 in dendritic cells was elevated via the DP pathway, but it was lowered by the CRTH2 pathway. Collectively, PGD2 signals through CRTH2 to mediate CHS inflammation, and conversely, DP signals to exert inhibitory effects on CHS. Thus, we report opposing functions for PGD2 that depend on receptor usage in allergic reactions.
authors.affiliation: Department of Dermatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Shinobu
authors.initials: S
authors.lastname: Otani
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Kinya
authors.initials: K
authors.lastname: Nagata
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yokozeki
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Satoh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D018925:Chemokines; D016207:Cytokines; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor / Q000235:genetics; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015230:Prostaglandin D2 / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory
chemical_list: D018925:Chemokines; D016207:Cytokines; D020381:Interleukin-17; D053583:Interleukin-1beta; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C527097:prostanoid D receptor 1, mouse; D016753:Interleukin-10; D018664:Interleukin-12; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor