title: Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor.
abstract: PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.
authors.affiliation: Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. tasa1688.derm@tmd.ac.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Satoh
authors.forename: Rie
authors.initials: R
authors.lastname: Moroi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kanai
authors.forename: Koji
authors.initials: K
authors.lastname: Sumi
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yokozeki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Kinya
authors.initials: K
authors.lastname: Nagata
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hara
authors.forename: Masanori
authors.initials: M
authors.lastname: Utsuyama
authors.forename: Katsuiku
authors.initials: K
authors.lastname: Hirokawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nishioka
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D002908:Chronic Disease; D017449:Dermatitis, Allergic Contact / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015230:Prostaglandin D2 / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D007073:Immunoglobulin E; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor