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首页> 外文期刊>The biochemical journal >Interferons activate the p42/44 mitogen-activated protein kinase and JAK-STAT (Janus kinase-signal transducer and activator transcription factor) signalling pathways in hepatocytes: differential regulation by acute ethanol via a protein kinase C-dependent mechanism
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Interferons activate the p42/44 mitogen-activated protein kinase and JAK-STAT (Janus kinase-signal transducer and activator transcription factor) signalling pathways in hepatocytes: differential regulation by acute ethanol via a protein kinase C-dependent mechanism

机译：干扰素在肝细胞中激活p42 / 44丝裂丝溶蛋白激酶和jak-stat（Janus激酶 - 信号传感器和活化剂转录因子）信号通路：通过蛋白激酶C依赖机制通过急性乙醇进行差异调节

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pInterferons (IFNs) have been used in the treatment of viral hepatitis. However, their effectiveness is much reduced (& 10%) in alcoholics. The mechanism underlying this resistance remains unknown. Here, we report that IFN-α/β and IFN-γ rapidly activate the JAK-STAT1 (Janus kinase-signal transducer and activator transcription factor 1) and p42/44 mitogen-activatedprotein kinase (p42/44 MAPK) in freshly isolated rat hepatocytes. Treatment of hepatocytes with 25-100 mM ethanol for 30 min inhibited IFN-β- or IFN-γ-induced STAT1 activation and tyrosine phosphorylation. The inhibitory effect of ethanol was not reversed by pretreatment with either sodium vanadate, a non-selective tyrosine phosphatase inhibitor, or with MG132, a specific proteasome inhibitor. This suggests that protein tyrosine phosphatases or the ubiquitin-proteasome pathway are not involved in the inhibitory action of ethanol. In contrast with the JAK-STAT signalling pathway, acute ethanol exposure significantly potentiated IFN-β or IFN-γ-induced activation of p42/44 MAPK, and caused marked activation of protein kinase C (PKC). Inhibition of PKC partially antagonized ethanol attenuation of IFN-induced STAT1 activation, suggesting that PKC may be involved. Taken together, these findings suggest that the ability of biologically relevant concentrations of ethanol (less than 100 mM) to markedly inhibit IFN-activated STAT1 is one of the cellular mechanisms responsible for the observed resistance of IFN therapy in alcoholics./p
机译：>干扰素（IFNS）已用于治疗病毒性肝炎。然而，它们的有效性在酗酒者中减少了（＆lt 19％）。这种阻力的机制仍然未知。在这里，我们报告IFN-α/β和IFN-γ在新鲜分离的大鼠中快速激活JAK-STAT1（Janus激酶 - 信号传感器和活化剂转录因子1）和P42 / 44丝裂原激活蛋白激酶（P42 / 44 mapk）肝细胞。用25-100mM乙醇处理肝细胞30分钟抑制IFN-β-或IFN-γ-诱导的Stat1活化和酪氨酸磷酸化。通过用钒酸钠，非选择性酪氨酸磷酸酶抑制剂或MG132，特定的蛋白酶体抑制剂，乙醇的抑制作用不会通过预处理而逆转。这表明蛋白质酪氨酸磷酸酶或泛素 - 蛋白酶体途径不参与乙醇的抑制作用。与Jak-Stat信令途径相比，急性乙醇暴露显着增强IFN-β或IFN-γ诱导的P42 / 44 MAPK活化，并引起了蛋白激酶C（PKC）的标记激活。 PKC抑制PKC部分拮抗IFN诱导的STAT1活化的乙醇衰减，表明PKC可能涉及。这些发现表明，生物相关浓度乙醇（小于100mm）明显抑制IFN活化的STAT1的能力是负责IFN治疗在酗酒者中的抗性的细胞机制之一。

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