ono-ae-248 and Dermatitis--Contact

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.. We sought to investigate whether PGE(2)-EP(3) signaling exerts anti-inflammatory actions in skin allergic inflammation.. 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.. 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.. PGE(2)-EP(3) signaling inhibits keratinocytes activation and exerts anti-inflammatory actions in murine CHS.

Topics: Animals; Chemokine CXCL1; Dermatitis, Contact; Dinitrofluorobenzene; Dinoprostone; Disease Models, Animal; Female; Gene Expression; Humans; Keratinocytes; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Signal Transduction; Skin; Tumor Necrosis Factor-alpha