Analysis of IFN-γ-Induced Cell Cycle Arrest and Cell Death in Hepatocytes

抄録

The mechanism by which IFN- γinduces 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- γinduced cell cycle arrest at the initial stage, followed by cell death. A protein synthesis inhibitor, cycloheximide, significantly inhibited cell death, implying that IFN-γinduces 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- γalso 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 conclu-sion, 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.