Geriatrics Digestion Department of Internal Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
J Med Virol. 2018 Jun;90(6):1112-1120. doi: 10.1002/jmv.25053. Epub 2018 Mar 12.
Alcohol could compromise the anti-hepatitis C virus (HCV) function of interferon-alpha (IFN-α). However, little information is available about the effect of alcohol on interferon-lambda (IFN-λ, type III IFN), a novel candidate for development of therapy for HCV infection. Huh7 cells were infected with HCV JFH-1 virus, then treated with alcohol, and/or IFN-λ1. RT-PCR and Western blot were used to detect the levels of HCV and key cellular factors. Overexpression or silencing expression was performed to verify the role of key factors in alcohol-attenuated anti-HCV function of IFN-λ1. Alcohol treatment compromised anti-HCV effect of IFN-λ1 in HCV JFH-1-infected Huh7 cells, evidenced by the significantly increased levels of HCV RNA, and HCV core protein in alcohol-/IFN-λ1-treated cells compared to cells with IFN-λ1 treatment alone. Investigation of the mechanisms responsible for the alcohol action revealed that alcohol enhanced the expression of protein inhibitor of activated STAT (PIASy). Overexpression of PIASy compromised anti-HCV ability of IFN-λ1, whereas silencing expression of PIASy partly restored the alcohol-attenuated anti-HCV effect of IFN-λ1. More importantly, overexpression of PIASy significantly down-regulated the level of IFN-λ1-indcued phosphorylation of STAT1 (p-STAT1), an important adaptor in IFN-λ pathway, as well as reduced the expression of IFN-λ1-induced IFN-stimulated genes 56 (ISG56), and myxovirus resistance 1 (Mx1), two antiviral effectors in in IFN-λ pathway. These findings indicate that alcohol, through inducing the expression of negative regulator in IFN-λ pathway, inhibits IFN-λ-mediated anti-HCV action in human hepatic cells, which may lead to the poor efficacy of IFN-λ-based therapy against HCV infection.
酒精可能会损害干扰素-α（IFN-α）的抗丙型肝炎病毒（HCV）功能。然而，关于酒精对干扰素-λ（IFN-λ，III 型干扰素）的影响知之甚少，干扰素-λ是开发治疗丙型肝炎病毒感染的新候选药物。将 Huh7 细胞用 HCV JFH-1 病毒感染，然后用酒精和/或 IFN-λ1 处理，用 RT-PCR 和 Western blot 检测 HCV 和关键细胞因子的水平。通过过表达或沉默表达来验证关键因素在酒精减弱 IFN-λ1 抗 HCV 功能中的作用。酒精处理削弱了 HCV JFH-1 感染的 Huh7 细胞中 IFN-λ1 的抗 HCV 作用，这表现在与 IFN-λ1 单独处理的细胞相比，酒精/IFN-λ1 处理的细胞中 HCV RNA 和 HCV 核心蛋白的水平显著增加。对酒精作用的机制研究表明，酒精增强了蛋白抑制物激活 STAT（PIASy）的表达。过表达 PIASy 削弱了 IFN-λ1 的抗 HCV 能力，而沉默表达 PIASy 部分恢复了酒精减弱的 IFN-λ1 的抗 HCV 作用。更重要的是，过表达 PIASy 显著下调了 IFN-λ1 诱导的 STAT1（p-STAT1）磷酸化水平，STAT1 是 IFN-λ 途径中的一个重要衔接蛋白，以及 IFN-λ1 诱导的 IFN 刺激基因 56（ISG56）和流感病毒抗性 1（Mx1）的表达，IFN-λ 途径中的两种抗病毒效应物。这些发现表明，酒精通过诱导 IFN-λ 途径中的负调节因子的表达，抑制了人肝细胞中 IFN-λ 介导的抗 HCV 作用，这可能导致基于 IFN-λ 的治疗对 HCV 感染的疗效不佳。
