Inhibition of phosphodiesterase 7A ameliorates Concanavalin A-induced hepatitis in mice.
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.
Goto
Megumi
M
Biomedical Research Laboratories, Asubio Pharma Co., Limited, Osaka, Japan.
Tanaka
Yoshitaka
Y
Murakawa
Masao
M
Kadoshima-Yamaoka
Kumiko
K
Inoue
Hidekazu
H
Murafuji
Hidenobu
H
Nagahira
Asako
A
Kanki
Satomi
S
Hayashi
Yasuhiro
Y
Nagahira
Kazuhiro
K
Ogata
Atsuto
A
Miura
Kenju
K
Nakatsuka
Takashi
T
Chamoto
Kenji
K
Fukuda
Yoshiaki
Y
Nishimura
Takashi
T
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
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