Induction of tumor necrosis factor α production by human hepatocytes in chronic viral hepatitis

Abstract

Tumor necrosis factor α (TNF-α) is a multifunctional cytokine that has an important role in the pathogenesis of inflammation, cachexia, and septic shock. Although TNF-α is mainly produced by macrophages, there is evidence regarding TNF-α production by cells that are not derived from bone marrow. TNF-α production by normal and inflamed human liver was assessed at both mRNA and protein levels. Using a wide panel of novel anti-TNF-α monoclonal antibodies and a specific polyclonal antiserum, TNF-α immunoreactivity was found in hepatocytes from patients chronically infected with either hepatitis B virus (HBV) or hepatitis C virus. Minimal TNF-α immunoreactivity was detected in the mononuclear cell infiltrate and Kupffer cells. In situ hybridization experiments using a TNF-α RNA probe showed a significant expression of TNF-α mRNA in hepatocytes, Kupffer cells, and some infiltrating mononuclear cells. By contrast, TNF-α was detected at low levels in liver biopsies from normal individuals or patients with alcoholic liver disease and low expression of TNF-α mRNA was observed in these specimens. Transfection of HepG2 hepatoblastoma cells with either HBV genome or HBV X gene resulted in induction of TNF-α expression. Our results demonstrate that viral infection induces, both in vivo and in vitro, TNF-α production in hepatocytes, and indicate that the HBV X protein may regulate the expression of this cytokine. These findings suggest that TNF-α may have an important role in human liver diseases induced by viruses.