Fas system and apoptosis in viral hepatitis

Abstract

Hepatitis C virus (HCV) and hepatitis B virus (HBV) are the major causative agents of chronic liver disease. However, the mechanisms responsible for liver cell injury remain to be clarified. Playing crucial roles in the clearance of viral infection are cytotoxic T lymphocytes. Recently, it has been demonstrated that perforin- and Fas-based mechanisms account for all T cell-mediated cytotoxicity. Therefore, we examined the correlation between liver cell damage and the Fas system in the liver of patients with chronic hepatitis C. Fas is a cell surface protein that mediates apoptosis with treatment of the Fas ligand or the anti-Fas antibody. To investigate the role of Fas in type C hepatitis, we examined the correlation between liver cell damage and Fas expression. Fas expression was found mainly in the cytoplasm of hepatocytes and these positive cells were found particularly among infiltrating lymphocytes. A high prevalence of Fas expression was shown in liver tissue with more severe inflammation. The Fas system-mediated death signal requires the interaction of Fas ligand with Fas on target cells. We isolated a 1.9 kb cDNA clone for the human Fas ligand and examined the expression of the Fas ligand in liver-infiltrating mononuclear cells obtained from patients with chronic hepatitis C. The open reading frame encodes 281 amino acids. Next, we examined the expression of the Fas ligand in liver-infiltrating mononuclear cells obtained from patients with chronic hepatitis C. The amplified products (231 bp) derived from Fas ligand transcripts were detected in liver-infiltrating mononuclear cells, whereas no signal was observed in liver tissues. In HCV infection, Fas expression in hepatocytes is up-regulated in accordance with the severity of liver inflammation. When HCV-specific T cells migrate into 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 system plays an important role in liver cell injury by HCV infection.