Interferon-gamma induces reactive oxygen species and endoplasmic reticulum stress at the hepatic apoptosis

J Cell Biochem. 2003 May 15;89(2):244-53. doi: 10.1002/jcb.10501.


Interferon-gamma (IFN-gamma) induces cell-cycle arrest and p53-independent apoptosis in primary cultured hepatocytes. However, the detailed mechanism, including regulating molecules, is still unclear. In this study, we found that IFN-gamma induced generation of reactive oxygen species (ROS) in primary hepatocytes and that pyrrolidinedithiocarbamate (PDTC), an anti-oxidant reagent, completely suppressed IFN-gamma-induced hepatic apoptosis. PDTC blocked apoptosis downstream from IRF-1 and upstream from caspase activation, suggesting that the generation of ROS occurred between these stages. However, IFN-gamma also induced the generation of ROS in IRF-1-deficient hepatocytes, cells insensitive to IFN-gamma-induced apoptosis. Moreover, a general cyclooxygenase (COX) inhibitor, indomethacin (but not the cyclooxygenase 2-specific inhibitor, NS-398) also inhibited the apoptosis without blocking the generation of ROS. Both PDTC and indomethacin also blocked IFN-gamma-induced release of cytochrome c from mitochondria. These results suggest that ROS are not the only or sufficient mediators of IFN-gamma-induced hepatic apoptosis. In contrast, we also found that IFN-gamma induced endoplasmic reticulum (ER) stress proteins, CHOP/GADD153 and caspase 12, in wild-type primary hepatocytes, but induced only caspase 12 and not CHOP/GADD153 protein in IRF-1-deficient hepatocytes. These results suggest that IFN-gamma induces ER stress in primary hepatocytes. Both the ROS and ER stress induced by IFN-gamma may be complementary mediators that induce apoptosis in primary hepatocytes.

MeSH terms

  • Apoptosis* / drug effects
  • Base Sequence
  • Blotting, Western
  • DNA Primers
  • Endoplasmic Reticulum / drug effects*
  • Indomethacin / pharmacology
  • Interferon-gamma / physiology*
  • Liver / cytology*
  • Liver / drug effects
  • Pyrrolidines / pharmacology
  • Reactive Oxygen Species*
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • Thiocarbamates / pharmacology


  • DNA Primers
  • Pyrrolidines
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid
  • Interferon-gamma
  • Indomethacin