Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Drug Alcohol Depend. 2010 Nov 1;112(1-2):107-16. doi: 10.1016/j.drugalcdep.2010.05.008. Epub 2010 Jun 20.
Alcohol drinking and hepatitis C virus (HCV) infection frequently coexist in patients with chronic liver disease. There is limited information, however, about the impact of alcohol on host cell innate immunity and full cycle replication of HCV. This study investigated whether alcohol impairs the intracellular innate immunity in human hepatocytes, promoting HCV infection and replication. Alcohol treatment of human hepatocytes before, during and after viral infection significantly enhanced full cycle HCV replication. Alcohol suppressed intracellular expression of type I interferons (IFN-α/β) in human hepatocytes. Investigation of the mechanisms responsible for the alcohol action revealed that alcohol inhibited the expression of the IFN regulatory factors (IRF-5 and IRF-7), and signal transducer and activator of transcription (STAT-1 and STAT-2), the key positive regulators in type I IFN signaling pathway. In addition, alcohol induced the expression of suppressors of cytokine signaling (SOCS-2 and SOCS-3), the key negative regulators of IFN-α/β expression. These in vitro findings suggest that alcohol, through modulating the expression of key regulators in IFN signaling pathway, inhibits type I IFN-based intracellular innate immunity in hepatocytes, which may contribute to the chronicity of HCV infection and the poor efficacy of IFN-α-based therapy.
饮酒和丙型肝炎病毒（HCV）感染在慢性肝病患者中经常同时存在。然而，关于酒精对宿主细胞固有免疫和 HCV 全周期复制的影响的信息有限。本研究调查了酒精是否会损害人肝细胞中的细胞内固有免疫，从而促进 HCV 感染和复制。在病毒感染之前、期间和之后，用酒精处理人肝细胞会显著增强 HCV 的全周期复制。酒精抑制人肝细胞内 I 型干扰素（IFN-α/β）的表达。对酒精作用机制的研究表明，酒精抑制 IFN 信号通路关键正调控因子干扰素调节因子（IRF-5 和 IRF-7）和信号转导和转录激活因子（STAT-1 和 STAT-2）的表达。此外，酒精诱导细胞因子信号转导抑制因子（SOCS-2 和 SOCS-3）的表达，SOCS-2 和 SOCS-3 是 IFN-α/β表达的关键负调控因子。这些体外研究结果表明，酒精通过调节 IFN 信号通路中的关键调控因子，抑制肝细胞中基于 I 型 IFN 的细胞内固有免疫，这可能导致 HCV 感染的慢性化和 IFN-α 为基础的治疗效果不佳。
