Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
Antiviral Res. 2012 Nov;96(2):260-8. doi: 10.1016/j.antiviral.2012.09.002. Epub 2012 Sep 15.
Ribavirin in combination with interferon (IFN)-α is the approved treatment for hepatitis C virus (HCV) infection. Interference of ribavirin with signaling events is involved in its biological activities. However, little is known of signaling pathways induced by ribavirin following HCV infection. In human hepatoma cells, effects of ribavirin on ERK and signal transducers and activators of transcription (STAT) pathways, HCV replication, and antiviral gene expression were evaluated before and after cell culture-derived HCV infection. Ribavirin reduced phosphorylation of Raf, MEK, ERK, Tyk2, and STAT1, but selectively increased STAT3 phosphorylation. IFN-α synergistically regulated ERK and STAT3 phosphorylation with ribavirin, and up-regulated expression and phosphorylation of STAT1. Ribavirin dose-dependently decreased HCV RNA replication and HCV protein expression, with slight induction of IFN regulatory factor 9 and IFN-stimulated gene 15. Ribavirin and IFN-α exerted a synergetic inhibitory effect on HCV. ERK and STAT pathways were down-regulated by ribavirin following HCV infection. These results suggest that ribavirin may mediate anti-HCV activity through interference with ERK and STAT pathways.
利巴韦林联合干扰素（IFN）-α是批准用于治疗丙型肝炎病毒（HCV）感染的方法。利巴韦林对信号事件的干扰与其生物学活性有关。然而，对于 HCV 感染后利巴韦林诱导的信号通路知之甚少。在人肝癌细胞中，在细胞培养衍生的 HCV 感染前后评估了利巴韦林对 ERK 和信号转导和转录激活剂（STAT）途径、HCV 复制和抗病毒基因表达的影响。利巴韦林降低了 Raf、MEK、ERK、Tyk2 和 STAT1 的磷酸化，但选择性地增加了 STAT3 的磷酸化。IFN-α与利巴韦林协同调节 ERK 和 STAT3 的磷酸化，并上调 STAT1 的表达和磷酸化。利巴韦林剂量依赖性地降低 HCV RNA 复制和 HCV 蛋白表达，同时轻微诱导 IFN 调节因子 9 和 IFN 刺激基因 15。利巴韦林和 IFN-α对 HCV 表现出协同抑制作用。HCV 感染后，利巴韦林下调 ERK 和 STAT 途径。这些结果表明，利巴韦林可能通过干扰 ERK 和 STAT 途径来介导抗 HCV 活性。
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