Protective effect of hepatocyte growth factor on interferon-gamma-induced cytotoxicity in mouse hepatocytes

Hepatology. 1995 Jun;21(6):1585-93.


We examined the interactive effect of several cytokines (interleukin-1 beta [IL-1 beta], tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma], IL-6, IFN-alpha/beta, and hepatocyte growth factor [HGF]) presumably involved in hepatitis, on primary cultured murine hepatocytes. Among these cytokines, only IFN-gamma induced LDH release from hepatocytes in both time- and dose-dependent fashions. The cytotoxic effect was inhibited by antiserum-containing anti-mouse IFN-gamma monoclonal antibodies (R4-6A2). Moreover, intriguingly, IFN-gamma induced DNA fragmentation in the hepatocytes in a time- and dose-dependent fashion according to the gel electrophoresis of genomic DNA and flow cytometry analysis. These results suggest that the cytotoxic effect of IFN-gamma on hepatocytes was caused by inductive apoptosis. The LDH release and DNA fragmentation induced by IFN-gamma were inhibited by HGF in a dose-dependent manner, whereas they seemed to be accelerated by TNF-alpha. Flow cytometry analysis of the nuclei of treated hepatocytes confirmed the interactions in DNA degradation. The DNA synthesis of cultured hepatocytes was also reduced by IFN-gamma but recovered by hepatocyte growth factor. Taken together, IFN-gamma is presumed to be a critical cytokine in hepatic damage, and the network composed of IFN-gamma, TNF-alpha, and HGF may play an important role in the regulation of liver injury.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • DNA / analysis
  • DNA Damage*
  • Flow Cytometry
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology*
  • Kinetics
  • L-Lactate Dehydrogenase / analysis
  • Liver / cytology
  • Liver / drug effects*
  • Mice
  • Recombinant Proteins / toxicity
  • Time Factors


  • Antibodies, Monoclonal
  • Recombinant Proteins
  • Hepatocyte Growth Factor
  • Interferon-gamma
  • DNA
  • L-Lactate Dehydrogenase