Activation of nuclear factor kappa B in hepatitis C virus infection: Implications for pathogenesis and hepatocarcinogenesis

The hepatitis C virus (HCV) core protein is a multifunctional protein. It may bind to the death domain of tumor necrosis factor receptor 1 (TNFR1) and to the cytoplasmic tail of lymphotoxin-beta receptor, implying that it may be involved in the apoptosis and anti-apoptosis signaling pathways. In vitro studies have been inconclusive regarding its ability to inhibit or enhance TNF-alpha-induced apoptosis. To address this issue, electrophoretic mobility shift assay (EMSA) and immunohistochemical studies were used to show the activation of nuclear factor kappa B (NF-kappa B) in HCV-infected liver tissues and in HCV core-transfected cells. The activation of NF-kappa B was correlated with the apoptosis assays. The results showed that NF-kappa B activation could be shown in HCV-infected livers and HCV core-transfected cells, The data of EMSA correlated with those of immunohistochemical studies, which revealed a higher frequency of NF-kappa B nuclear staining in HCV-infected than in normal livers. NF-kappa B activation conferred resistance to TNF-alpha-induced apoptosis in HCV core-transfected cells. Inhibition of NF-kappa B activation by pyrrolidine dithiocarbamate sensitized them to TNF-alpha-induced apoptosis. These findings suggest that HCV infection may cause anti-apoptosis by activation of NF-kappa B and implicate a mechanism by which HCV may evade the host's immune surveillance leading to viral persistence and possibly to hepatocarcinogenesis.