IFN-γ (interferon-γ) modulates IFN-α therapy in chronic hepatitis C infection; however, the underlying mechanism remains unclear. Here we demonstrate that long-term (3–6 days) but not short-term (up to 1 day) IFN-γ treatment of human hepatoma Hep3B cells attenuates IFN-α activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3, but enhances IFN-γ and interleukin 6 activation of STATs. Prolonged exposure to IFN-γ also significantly induces STAT1 protein expression without affecting STAT2, STAT3 and ERK (extracellular-signal-regulated kinase) 1/2 protein expression. To determine the role of STAT1 protein overexpression in regulation of IFN-α signalling, Hep3B cells were stably transfected with wild-type STAT1. Overexpression of STAT1 via stable transfection enhances IFN-γ activation of STAT1, but surprisingly attenuates IFN-α activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation. This STAT1-mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant-negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-α activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-α-activated STAT2 translocation from IFN-α receptor 2 to IFN-α receptor 1, a critical step in IFN-α signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-γ, are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-γ treatment inhibits IFN-α-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-α treatment failure in hepatitis C patients.
Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C
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Svetlana RADAEVA, Barbara JARUGA, Won-Ho KIM, Theo HELLER, T. Jake LIANG, Bin GAO; Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C. Biochem J 1 April 2004; 379 (1): 199–208. doi: https://doi.org/10.1042/bj20031495
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