ABSTRACT

Tumor necrosis factorα (TNFα) and interferon-γ (IFN-γ) are known as the representative inflammatory factors. These cytoldnes have been thought to be involved in the pathogenesis of hepatitis. However the  substantial functions of these cytokines in the liver are still controversial.  For example, a number of evidence show that TNFα is a major mediator in hepatic injury.  However, recent researches have shed a light on the positive side of TNFα in the liver. Namely, evidence has been accumulating that TNFα is a growth factor for hepatocytes and plays an important role in liver regeneration. Where does this contradiction derive from ? and what is the substantial role of IFN-γ in hepatic injury ? In this review, I attempt to reconcile the apparent contradictory studies on the bases of the findings of ours and previous other investigators’ studies.

After careful examination, we found that IFN-γ induces cell cycle arrest via inducing p53 gene.  In addition, this cytokine also induces apoptosis in hepatocytes by inducing caspase activation, which is a critical pathway to trigger apoptosis.  Interestingly, TNFα shows the opposite effects in these pathways. TNFα synergizes with IFN-γ in the induction of caspases, which explains the synergistic cytotoxic effect of TNFα and IFN-γ. In contrast, surprisingly, TNFα antagonizes IFN-γ in the cell cycle regulation and promotes the cell proliferation. These results led us to re-evaluate the roles of TNFα and IFN-γ in the liver. TNFα has two opposite functions in hepatocytes, i.e, it enhances IFN-γ-induced hepatic apoptosis and also induces proliferation of hepatocytes in distinct pathway. IFN-γ is not an modifier of TNFα but the substantial cytotoxic factor and cell cycle arrester of hepatocytes These results give the plausible explanation to the questions above about the contradiction of the effect of TNFα and IFN-γ in vivo. The mechanisms of these effects on hepatocytes explain the function of the cytokines in vivo in the pathogenesis of hepatitis.