title: Prostaglandin E(2)-EP(3) signaling suppresses skin inflammation in murine contact hypersensitivity.
abstract: BACKGROUND
  Prostaglandin (PG) E(2) exerts a variety of actions through 4 G protein-coupled receptors designated as EP(1), EP(2), EP(3), and EP(4). We have reported that PGE(2) acts on EP(3) in airway epithelial cells and exerts anti-inflammatory actions in ovalbumin-induced murine allergic asthma. Although EP(3) is also expressed in skin and PGE(2) is produced abundantly during skin allergic inflammation, the role of PGE(2)-EP(3) signaling in skin allergic inflammation remains unknown.
  
  
  OBJECTIVE
  We sought to investigate whether PGE(2)-EP(3) signaling exerts anti-inflammatory actions in skin allergic inflammation.
  
  
  METHODS
  We used a murine contact hypersensitivity (CHS) model and examined the role of EP(3) by using an EP(3)-selective agonist, ONO-AE-248 (AE248), and EP(3)-deficient mice. The inflammation was evaluated by the thickness and histology of the hapten-challenged ear. Inflammation-associated changes in gene expression and effects of AE248 were examined by means of microarray analysis of the skin. Localization of EP(3) was examined by staining for beta-galactosidase knocked in at the EP(3) locus in EP(3)-deficient mice. EP(3) action was also examined in cultured keratinocytes.
  
  
  RESULTS
  Administration of AE248 during the elicitation phase significantly suppressed CHS compared with that seen in vehicle-treated mice. Microarray analysis revealed that administration of AE248 inhibited the gene expression of neutrophil-recruiting chemokines, including CXCL1, at the elicitation site. X-gal staining in EP(3)-deficient mice revealed EP(3) expression in keratinocytes, which was further confirmed by anti-EP(3) antibody in wild-type mice. In cultured keratinocytes AE248 suppressed CXCL1 production induced by TNF-alpha.
  
  
  CONCLUSIONS
  PGE(2)-EP(3) signaling inhibits keratinocytes activation and exerts anti-inflammatory actions in murine CHS.
authors.affiliation: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Honda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ueta
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miyachi
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004139:Dinitrofluorobenzene / Q000276:immunology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C121546:ONO AE 248; C545647:PTGER3 protein, human; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014409:Tumor Necrosis Factor-alpha; D004139:Dinitrofluorobenzene; D015232:Dinoprostone