title: ASB16165, a phosphodiesterase 7A inhibitor, reduces cutaneous TNF-alpha level and ameliorates skin edema in phorbol ester 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation model in mice.
abstract: Possible role of phosphodiesterase 7A (PDE7A) in skin inflammation was examined using ASB16165, a specific inhibitor for PDE7A. Epicutaneous application of phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ear resulted in induction of skin edema, and topical treatment with ASB16165 inhibited the induction of skin edema in a dose-dependent manner. The TPA challenge also increased the level of TNF-alpha at the application site, and the ASB16165 treatment reduced the TNF-alpha level in the skin. In addition, ASB16165 suppressed the production of TNF-alpha by human keratinocytes stimulated in vitro with TPA and calcium ionophore. Forskolin, an activator of adenylyl cyclase, as well as dibutyryl cAMP also showed inhibitory effect on the TNF-alpha production in the cells, suggesting involvement of cAMP in TNF-alpha generation. These results demonstrate that PDE7A might regulate TNF-alpha production in keratinocytes in a cAMP-dependent fashion. As immunostaining analysis revealed that PDE7A is expressed in the epidermis and TNF-alpha is known to contribute to the TPA-induced edema, it is possible that the inhibitory effect of ASB16165 on skin edema in mouse TPA-induced dermatitis model is mediated by suppression of TNF-alpha production. This is the first report suggesting the association of PDE7A with the function of keratinocytes. ASB16165 will be useful as an agent for skin inflammation in which TNF-alpha plays a pathogenic role (e.g. psoriasis).
authors.affiliation: Biomedical Research Laboratories, Asubio Pharma Co Limited, Osaka, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kadoshima-Yamaoka
authors.forename: Megumi
authors.initials: M
authors.lastname: Goto
authors.forename: Masao
authors.initials: M
authors.lastname: Murakawa
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yoshioka
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Inoue
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Murafuji
authors.forename: Satomi
authors.initials: S
authors.lastname: Kanki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagahira
authors.forename: Atsuto
authors.initials: A
authors.lastname: Ogata
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakatsuka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C539237:1-cyclohexyl-N-(6-(4-hydroxy-1-piperidinyl)-3-pyridinyl)-3-methyl-1H-thieno(2,3-c)pyrazole-5-carboxamide; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517459:Pde7a protein, mouse; D013755:Tetradecanoylphorbol Acetate