FAS SYSTEM AND APOPTOSIS IN VIRAL-HEPATITIS

Hepatitis C virus (HCV) and hepatitis B virus (HBV) are the major caus ative agents of chronic liver disease. However, the mechanisms respons ible for liver cell injury remain to be clarified. Playing crucial rol es in the clearance of viral infection are cytotoxic T lymphocytes. Re cently, it has been demonstrated chat perforin-and Fas-based mechanism s account for all T cell-mediated cytotoxicity. Therefore, we examined the correlation between liver cell damage and the Fas system in the l iver of patients with chronic hepatitis C. Pas is a cell surface prote in that mediates apoptosis with treatment of the Fas ligand or the ant i-l;as antibody. To investigate the role of Fas in type C hepatitis, w e examined the correlation between liver cell damage and Fas expressio n. Pas expression was found mainly in the cytoplasm of hepatocytes and these positive cells were found particularly among infiltrating lymph ocytes. A high prevalence of Fas expression was shown in liver tissue with more severe inflammation. The Fas system-mediated death signal re quires the interaction of Fas ligand with Fas on target cells. We isol ated a 1.9 kb cDNA clone for the human Fas ligand and examined the exp ression of the Fas ligand in liver-infiltrating mononuclear cells obta ined from patients with chronic hepatitis C. The open reading frame en codes 281 amino acids. Next, we examined the expression of the Pas lig and in liver-infiltrating mononuclear cells obtained from patients wit h chronic hepatitis C. The amplified products (231 bp) derived from Fa s ligand transcripts were detected in liver-infiltrating mononuclear c ells, whereas no signal was observed in liver tissues. In HCV infectio n, Fas expression in hepatocytes is up-regulated in accordance with th e severity of liver inflammation. When HCV-specific T cells migrate in to hepatocytes and recognize the viral antigen via the T cell receptor , they become activated and express Fas ligand that can transduce the apoptotic death signal to Fas-bearing hepatocytes. Thus, the Fas syste m plays an important role in liver cell injury by HCV infection.