Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins.
Machida K, Tsukiyama-Kohara K, Seike E, Tone S, Shibasaki F, Shimizu M, Takahashi H, Hayashi Y, Funata N, Taya C, Yonekawa H, Kohara M.
Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
Persistent hepatitis C virus
(HCV) infection often progresses to chronic hepatitis, cirrhosis, and hepatocellular
carcinoma. Numerous viruses have been reported to escape from apoptotic mechanism
to maintain persistent infection. In the present study, we characterized the
effect of HCV proteins on the Fas signal using HCV transgenic mice, which expressed
core, E1, E2, and NS2 proteins, regulated by the Cre/loxP switching system.
The transgene expression of HCV transgenic mice caused resistance to Fas antibody
stimulated lethality. Apoptotic cell death in the liver of HCV protein expressing
mice was significantly reduced compared with nonexpressing mice. Histopathological
analysis and DNA fragmentation analysis revealed that the HCV proteins suppressed
Fas-mediated apoptotic cell death. To identify the target pathway of HCV proteins,
we characterized caspase activity. The activation of caspase-9 and -3/7 but
not caspase-8 was
inhibited by HCV proteins. Cytochrome c release from mitochondria was inhibited
in HCV protein expressing mice. These results indicated that the expression
of HCV proteins may directly or indirectly inhibit Fas-mediated apoptosis and
death in mice by repressing the release of cytochrome c from mitochondria, thereby
suppressing caspase-9 and -3/7 activation. These results suggest that HCV may
cause persistent infection, as a result of
suppression of Fas-mediated cell death.
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