INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY HUMAN HEPATOCYTES IN CHRONIC VIRAL-HEPATITIS

Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine that has an important role in the pathogenesis of inflammation, cachex ia, and septic shock. Although TNF-alpha is mainly produced by macroph ages, there is evidence regarding TNF-alpha production by cells that a re not derived from bone marrow. TNF-alpha production by normal and in flamed human liver was assessed at both mRNA and protein levels. Using a wide panel of novel anti-TNF-alpha monoclonal antibodies and a spec ific polyclonal antiserum, TNF-alpha immunoreactivity was found in hep atocytes from patients chronically infected with either hepatitis B vi rus (HBV) or hepatitis C virus. Minimal TNF-alpha immunoreactivity was detected in the mononuclear cell infiltrate and Kupffer cells. In sit u hybridization experiments using a TNF-alpha RNA probe showed a signi ficant expression of TNF-alpha mRNA in hepatocytes, Kupffer cells, and some infiltrating mononuclear cells. By contrast, TNF-alpha was detec ted at low levels in liver biopsies from normal individuals or patient s with alcoholic liver disease and low expression of TNF-alpha mRNA wa s observed in these specimens. Transfection of HepG2 hepatoblastoma ce lls with either HBV genome or HBV X gene resulted in induction of TNF- alpha expression. Our results demonstrate that viral infection induces , both in vivo and in vitro, TNF-alpha production in hepatocytes, and indicate that the HBV X protein may regulate the expression of this cy tokine. These findings suggest that TNF-alpha may have an important ro le in human liver diseases induced by viruses.