Analysis of IFN-γ-induced cell cycle arrest and cell death in hepatocytes

The mechanism by which IFN-γ induces cell cycle arrest and cell death in primary cultured hepatocytes was examined. The cell death exhibits apoptotic characters such as the appearance of apoptotic bodies and DNA fragmentation. IFN-γ induced cell cycle arrest at the initial stage, followed by cell death. A protein synthesis inhibitor, cycloheximide, significantly inhibited cell death, implying that IFN-γ induces de novo proteins involved in the death of hepatocytes. One of the most important apoptosis-related proteins, p53, was induced by IFN-γ in hepatocytes in a dose- and time-dependent manner. Northern blot analysis demonstrated that IFN-γ enhanced p53 mRNA expression as well as p21(WAF1/Cip1/Sdi1) mRNA expression, which is mediated by the increased expression of the p53 protein. Interestingly, IFN-γ also induced cell death in p53-deficient hepatocytes. The cell death occurred rather earlier in p53-deficient cells than in normal hepatocytes. However, the cell death was not accompanied by apoptotic bodies. Therefore, IFN-γ-induced hepatocyte cell death is p53-independent, and p53 may contribute to the apoptotic characters. In conclusion, IFN-γ is supposed to cause cell cycle arrest by inducing p53 and p21(WAF1/Cip1/Sdi1), and it was demonstrated that IFN-γ induces p53-independent cell death in primary cultured hepatocytes.