Ribavirin Regulates Hepatitis C Virus Replication Through Enhancing Interferon-Stimulated Genes and Interleukin 8
Ribavirin Regulates Hepatitis C Virus Replication Through Enhancing Interferon-Stimulated Genes and Interleukin 8
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DOI：
10.1093/infdis/jis025
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发表时间：
2012-04-01
影响因子：
6.4
通讯作者：
Onji, Morikazu
中科院分区：
文献类型：
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作者：
Tokumoto, Yoshio;Hiasa, Yoichi;Onji, Morikazu
背景。利巴韦林（RBV）增强干扰素（IFN）对丙型肝炎病毒（HCV）的抗病毒作用的方式尚不清楚。我们在体内和体外研究了RBV是否改变ifn刺激基因（ISGs）。我们测量了接受ifn - α治疗或不接受RBV治疗的HCV感染患者T淋巴细胞中ISGs的信使RNA （mRNA）水平。我们将RBV和/或ifn - α加入到基于质粒的HCV复制系统中，该系统在HepG2和Huh7细胞系中含有全长HCV基因型la序列，在Huh7细胞系中含有JFH-1 HCV基因型2a序列，并测量了isg和自分泌ifn - β的水平。在体内和体外实验中，ifn - α和RBV对蛋白激酶R和黏液病毒抗性A mRNA表达的增强作用强于ifn - α单独作用。这种增强依赖于自分泌ifn - β被RBV增强。在缺乏ifn - α的情况下，RBV上调白细胞介素8 （IL-8）。RBV诱导的IL-8上调与激活蛋白1 （activator protein 1, AP-1）的激活有关。利巴韦林通过增强自分泌ifn - β来增强isg诱导的ifn - α的抗hcv作用。此外，RBV可通过激活AP-1来增强IL-8。进一步了解RBV对ISG的调节将有助于建立一种消除HCV的方法。
Background. The manner in which ribavirin (RBV) enhances the antiviral effects of interferon (IFN) against hepatitis C virus (HCV) remains unknown. We investigated whether RBV modifies IFN-stimulated genes (ISGs) in vivo and in vitro.Methods. We measured the messenger RNA (mRNA) levels of ISGs in T lymphocytes from patients with HCV infection who were receiving IFN-alpha therapy with or without RBV. We added RBV and/or IFN-alpha to a plasmid-based HCV replication system containing a full-length HCV genotype la sequence in HepG2 and Huh7 cell lines and the JFH-1 HCV genotype 2a sequence in Huh7 cell lines and measured levels of ISGs and autocrine IFN-beta.Results. The expression of protein kinase R and myxovirus resistance A mRNA was enhanced more with IFN-alpha and RBV than by IFN-alpha alone in assays in vivo and in vitro. Such enhancement depended on autocrine IFN-beta being enhanced by RBV. RBV upregulated interleukin 8 (IL-8) in the absence of IFN-alpha. The IL-8 upregulation induced by RBV was responsible for the activation of activator protein 1 (AP-1).Conclusions. Ribavirin augments the anti-HCV effects of IFN-alpha induced by ISGs through enhancing autocrine IFN-beta. Moreover, RBV can enhance IL-8 through activating AP-1. Improved understanding of ISG modulation by RBV would help to establish a means of eliminating HCV.