Zhang Ting, Li Yuan, Lai Jian-Ping, Douglas Steven D, Metzger David S, O'Brien Charles P, Ho Wen-Zhe
Division of Allergy and Immunology, Joseph Stokes Jr. Research Institute at The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Hepatology. 2003 Jul;38(1):57-65. doi: 10.1053/jhep.2003.50295.
Alcohol consumption accelerates liver damage and diminishes the anti-hepatitis C virus (HCV) effect of interferon alfa (IFN-alpha) in patients with HCV infection. It is unknown, however, whether alcohol enhances HCV replication and promotes HCV disease progression. The availability of the HCV replicon containing hepatic cells has provided a unique opportunity to investigate the interaction between alcohol and HCV replicon expression. We determined whether alcohol enhances HCV RNA expression in the replicon containing hepatic cells. Alcohol, in a concentration-dependent fashion, significantly increased HCV replicon expression. Alcohol also compromised the anti-HCV effect of IFN-alpha. Investigation of the mechanism(s) responsible for the alcohol action on HCV replicon indicated that alcohol activated nuclear factor kappaB (NF-kappaB) promoter. Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-kappaB, abolished alcohol-induced HCV RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on HCV replicon expression. In conclusion, alcohol, probably through the activation of NF-kappaB and the endogenous opioid system, enhances HCV replicon expression and compromises the anti-HCV effect of IFN-alpha. Thus, alcohol may play an important role in vivo as a cofactor in HCV disease progression and compromise IFN-alpha-based therapy against HCV infection.
饮酒会加速肝脏损伤，并降低丙型肝炎病毒（HCV）感染患者中干扰素α（IFN-α）的抗丙型肝炎病毒作用。然而，尚不清楚酒精是否会增强HCV复制并促进HCV疾病进展。含有HCV复制子的肝细胞的可获得性为研究酒精与HCV复制子表达之间的相互作用提供了独特的机会。我们确定了酒精是否会增强含有复制子的肝细胞中的HCV RNA表达。酒精以浓度依赖的方式显著增加了HCV复制子的表达。酒精还削弱了IFN-α的抗HCV作用。对酒精作用于HCV复制子的机制的研究表明，酒精激活了核因子κB（NF-κB）启动子。咖啡酸苯乙酯（CAPE）是NF-κB激活的特异性抑制剂，它消除了酒精诱导的HCV RNA表达。此外，阿片受体拮抗剂纳曲酮消除了酒精对HCV复制子表达的增强作用。总之，酒精可能通过激活NF-κB和内源性阿片系统，增强HCV复制子表达并削弱IFN-α的抗HCV作用。因此，酒精在体内可能作为HCV疾病进展的辅助因子发挥重要作用，并损害基于IFN-α的抗HCV感染治疗。
