title: Inhibition of phosphodiesterase 7A ameliorates Concanavalin A-induced hepatitis in mice.
abstract: An intravenous injection of Concanavalin A (Con A) elevated the serum level of alanine aminotransferase (ALT) activity, a marker for liver damage, and an oral administration of PDE7A inhibitor SUN11817 suppressed the increase of ALT activity in a dose-dependent manner. Histological analysis revealed that Con A injection caused extensive liver damage, and that the SUN11817 treatment improved the degenerative change in the liver. In addition, SUN11817 inhibited not only the production of IL-4 and TNF-alpha in the Con A-induced hepatitis model but also that in vitro by murine splenocytes stimulated with alpha-galactosylceramide, an activator specific for NKT cells. The Con A injection to mice also induced expression of Fas ligand (FasL) on NKT cells, which was significantly prevented by SUN11817. As NKT cells are known to contribute to the pathogenesis in Con A-induced hepatitis by producing cytokines such as IL-4 and TNF-alpha and inducing FasL-mediated hepatocyte injury, it is thought that PDE7A inhibitor SUN11817 improves liver injury in the Con A model by blocking cytokine production and FasL expression in NKT cells. PDE7A might be a novel pharmaceutical target for hepatitis.
authors: Biomedical Research Laboratories, Asubio Pharma Co., Limited, Osaka, Japan.
authors: Megumi
authors: M
authors: Goto
authors: Yoshitaka
authors: Y
authors: Tanaka
authors: Masao
authors: M
authors: Murakawa
authors: Kumiko
authors: K
authors: Kadoshima-Yamaoka
authors: Hidekazu
authors: H
authors: Inoue
authors: Hidenobu
authors: H
authors: Murafuji
authors: Asako
authors: A
authors: Nagahira
authors: Satomi
authors: S
authors: Kanki
authors: Yasuhiro
authors: Y
authors: Hayashi
authors: Kazuhiro
authors: K
authors: Nagahira
authors: Atsuto
authors: A
authors: Ogata
authors: Kenju
authors: K
authors: Miura
authors: Takashi
authors: T
authors: Nakatsuka
authors: Kenji
authors: K
authors: Chamoto
authors: Yoshiaki
authors: Y
authors: Fukuda
authors: Takashi
authors: T
authors: Nishimura
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002452:Cell Count; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D003208:Concanavalin A; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D015847:Interleukin-4 / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: C546034:1-cyclohexyl-N-(3-fluoro-4-(4-methyl-1-piperazinyl)phenyl)-3-methyl-1H-thieno(2,3-c)pyrazole-5-carboxamide; D053222:Fas Ligand Protein; D005699:Galactosylceramides; D011720:Pyrazoles; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D003208:Concanavalin A; D015847:Interleukin-4; D000410:Alanine Transaminase; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517459:Pde7a protein, mouse