Interferon‐γ induces reactive oxygen species and endoplasmic reticulum stress at the hepatic apoptosis

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Abstract
Interferon‐γ (IFN‐γ) 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‐γ induced generation of reactive oxygen species (ROS) in primary hepatocytes and that pyrrolidinedithiocarbamate (PDTC), an anti‐oxidant reagent, completely suppressed IFN‐γ‐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‐γ also induced the generation of ROS in IRF‐1‐deficient hepatocytes, cells insensitive to IFN‐γ‐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‐γ‐induced release of cytochrome c from mitochondria. These results suggest that ROS are not the only or sufficient mediators of IFN‐γ‐induced hepatic apoptosis. In contrast, we also found that IFN‐γ 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‐γ induces ER stress in primary hepatocytes. Both the ROS and ER stress induced by IFN‐γ may be complementary mediators that induce apoptosis in primary hepatocytes. J. Cell. Biochem. 89: 244–253, 2003.