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首页> 外文期刊>The Biochemical Journal >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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Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C

机译：干扰素-γ抑制肝细胞中的干扰素-α信号传导：慢性丙型肝炎涉及STAT1诱导和STAT1过表达的证据

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摘要

IFN-gamma (interferon-gamma) modulates IFN-alpha 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-gamma treatment of human hepatoma Hep3B cells attenuates IFN-alpha activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3. but enhances IFN-gamma and interleukin 6 activation of STATs. Prolonged exposure to IFN-gamma 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 ill regulation of IFN-alpha signalling, Hep3B cells were stably transfected with wild-type STAT1. Over-expression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1, but surprisingly attenuates IFN-alpha 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-alpha activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-alpha-activated STAT2 translocation from IFN-alpha receptor 2 to IFN-alpha receptor 1, a critical step in IFN-alpha signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-gamma are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-gamma treatment inhibits IFN-alpha-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-alpha treatment failure in hepatitis C patients.
机译：IFN-γ（干扰素-γ）调节慢性丙型肝炎感染中的IFN-α治疗：但是，其潜在机制仍不清楚。在这里，我们证明人类肝癌Hep3B细胞的长期（3-6天）而非短期（至1天）IFN-γ治疗可减弱STAT1的IFN-α激活（信号转导子和转录因子1的激活子）。 ，STAT2和STAT3。但会增强STAT的IFN-γ和白介素6激活。长时间暴露于IFN-γ也会显着诱导STAT1蛋白表达，而不会影响STAT2，STAT3和ERK（细胞外信号调节激酶）1/2蛋白的表达。为了确定STAT1蛋白过表达对IFN-α信号调节的不良作用，用野生型STAT1稳定转染了Hep3B细胞。 STAT1通过稳定转染的过表达增强了STAT1的IFN-γ激活，但出人意料地减弱了STAT1，STAT2和STAT3的IFN-α激活，而不会影响Janus激酶的激活。这种STAT1介导的抑制作用不需要STAT1酪氨酸磷酸化，因为在酪氨酸残基701上存在突变的显性阴性STAT1的过表达也阻断了STAT1，STAT2和STAT3的IFN-α激活。此外，STAT1的过表达会阻止IFN-α激活的STAT2从IFN-α受体2转移到IFN-α受体1，这是IFN-α信号激活的关键步骤。最后，与健康对照组相比，大多数丙型肝炎病毒感染的肝脏中检测到的STAT1蛋白表达水平明显较高，这可能是由IFN-γ诱导的。总之，长期的IFN-γ治疗很可能至少部分地通过诱导STAT1蛋白表达抑制IFN-α激活的信号，这可能部分导致丙型肝炎患者的IFN-α治疗失败。

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