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: Megumi Goto, Yoshitaka Tanaka, Masao Murakawa, Kumiko Kadoshima-Yamaoka, Hidekazu Inoue, Hidenobu Murafuji, Asako Nagahira, Satomi Kanki, Yasuhiro Hayashi, Kazuhiro Nagahira, Atsuto Ogata, Kenju Miura, Takashi Nakatsuka, Kenji Chamoto, Yoshiaki Fukuda, Takashi Nishimura
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 9 Issue 11 Pg. 1347-51 (Oct 2009) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 19671449 (Publication Type: Journal Article)

Chemical References

• 1-cyclohexyl-N-(3-fluoro-4-(4-methyl-1-piperazinyl)phenyl)-3-methyl-1H-thieno(2,3-c)pyrazole-5-carboxamide
• Fas Ligand Protein
• Galactosylceramides
• Pyrazoles
• Thiophenes
• Tumor Necrosis Factor-alpha
• alpha-galactosylceramide
• Concanavalin A
• Interleukin-4
• Alanine Transaminase
• Cyclic Nucleotide Phosphodiesterases, Type 7
• Pde7a protein, mouse

Topics

• Alanine Transaminase (blood)
• Animals
• Cell Count
• Chemical and Drug Induced Liver Injury (drug therapy, pathology)
• Concanavalin A
• Cyclic Nucleotide Phosphodiesterases, Type 7 (antagonists & inhibitors)
• Fas Ligand Protein (metabolism)
• Female
• Galactosylceramides (pharmacology)
• Interleukin-4 (blood, metabolism)
• Liver (cytology, drug effects)
• Mice
• Mice, Inbred C57BL
• Natural Killer T-Cells (drug effects, metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• Spleen (drug effects, metabolism)
• Thiophenes (pharmacology, therapeutic use)
• Tumor Necrosis Factor-alpha (blood, metabolism)