Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, MD 20892, USA.
Hepatology. 2012 Dec;56(6):2060-70. doi: 10.1002/hep.25897. Epub 2012 Nov 19.
Early, vigorous intrahepatic induction of interferon (IFN)-stimulated gene (ISG) induction is a feature of hepatitis C virus (HCV) infection, even though HCV inhibits the induction of type I IFNs in vitro. To identify the cytokines and cells that drive ISG induction and mediate antiviral activity during acute HCV infection, type I and III IFN responses were studied in (1) serial liver biopsies and plasma samples obtained from 6 chimpanzees throughout acute HCV infection and (2) primary human hepatocyte (PHH) cultures upon HCV infection. Type I IFNs were minimally induced at the messenger RNA (mRNA) level in the liver and were undetectable at the protein level in plasma during acute HCV infection of chimpanzees. In contrast, type III IFNs, in particular, interleukin (IL)-29 mRNA and protein, were strongly induced and these levels correlated with ISG expression and viremia. However, there was no association between intrahepatic or peripheral type III IFN levels and the outcome of acute HCV infection. Infection of PHH with HCV recapitulated strong type III and weak type I IFN responses. Supernatants from HCV-infected PHH cultures mediated antiviral activity upon transfer to HCV-replicon-containing cells. This effect was significantly reduced by neutralization of type III IFNs and less by neutralization of type I IFNs. Furthermore, IL-29 production by HCV-infected PHH occurred independently from type I IFN signaling and was not enhanced by the presence of plasmacytoid dendritic cells.
Hepatocyte-derived type III IFNs contribute to ISG induction and antiviral activity, but are not the principal determinant of the outcome of HCV infection.
早期、强烈的肝内干扰素（IFN）刺激基因（ISG）诱导是丙型肝炎病毒（HCV）感染的一个特征，尽管 HCV 在体外抑制 I 型 IFN 的诱导。为了鉴定在 HCV 感染期间驱动 ISG 诱导和介导抗病毒活性的细胞因子和细胞，研究了 I 型和 III 型 IFN 反应：（1）从 6 只感染 HCV 的黑猩猩整个急性 HCV 感染期间获得的肝活检和血浆样本；（2）HCV 感染后的原代人肝细胞（PHH）培养物。在 HCV 感染的黑猩猩中，I 型 IFN 在肝内仅在信使 RNA（mRNA）水平上被轻微诱导，在血浆中无法检测到蛋白水平。相比之下，III 型 IFN 强烈诱导，特别是白细胞介素（IL）-29 mRNA 和蛋白，这些水平与 ISG 表达和病毒血症相关。然而，肝内或外周 III 型 IFN 水平与急性 HCV 感染的结果之间没有关联。HCV 感染 PHH 可重现强烈的 III 型和弱的 I 型 IFN 反应。从 HCV 感染的 PHH 培养物上清中转移到含有 HCV 复制子的细胞中可介导抗病毒活性。通过中和 III 型 IFNs 显著降低了这种作用，而通过中和 I 型 IFNs 则降低较少。此外，HCV 感染的 PHH 产生的 IL-29 发生在 I 型 IFN 信号之外，并且不会因浆细胞样树突状细胞的存在而增强。
肝源性 III 型 IFNs 有助于 ISG 诱导和抗病毒活性，但不是 HCV 感染结果的主要决定因素。
