Unit of Viral Hepatitis, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Eur J Immunol. 2012 Sep;42(9):2374-82. doi: 10.1002/eji.201242388.
Type I interferons (IFNs), including IFN-α, -β, and -ω, play a critical role in innate immune responses against viral infection. IFN-λ, including IL-29, IL-28A, and IL-28B, recently identified as a new subfamily of IFN named type III IFN, has also been demonstrated to suppress virus replication in vitro and in vivo. However, the molecular mechanisms that regulate the induction of type III IFNs during viral infection remain elusive. Here, we demonstrate that IL-28 (IFN-λ 2/3) IFN production, similar to type I IFN, represents a primary and direct host response to HCV genomic RNA transfection. IL-28 (IFN-λ2/3) induction by HCV genomic RNA was dependent upon the activation of NF-κB and IRF3. We identified a minimal IL-28 promoter region consisting of putative NF-κB and IRF3-binding sites. Furthermore, we showed that HCV infection can inhibit HCV genomic RNA-induced IL-28 expression, and that the viral NS3/4A protease activity was responsible for this inhibitory effect. Our results present important evidence for the control of type III IFN response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
I 型干扰素（IFNs），包括 IFN-α、-β 和 -ω，在抗病毒感染的先天免疫反应中发挥关键作用。IFN-λ，包括 IL-29、IL-28A 和 IL-28B，最近被鉴定为 IFN 的一个新的亚家族，称为 III 型 IFN，也已被证明可在体外和体内抑制病毒复制。然而，调节病毒感染期间 III 型 IFN 诱导的分子机制仍不清楚。在这里，我们证明了与 I 型 IFN 相似，IL-28（IFN-λ2/3）IFN 的产生代表了对 HCV 基因组 RNA 转染的主要和直接的宿主反应。HCV 基因组 RNA 诱导的 IL-28（IFN-λ2/3）诱导依赖于 NF-κB 和 IRF3 的激活。我们确定了一个由潜在的 NF-κB 和 IRF3 结合位点组成的最小的 IL-28 启动子区域。此外，我们表明 HCV 感染可以抑制 HCV 基因组 RNA 诱导的 IL-28 表达，而病毒 NS3/4A 蛋白酶活性是这种抑制作用的原因。我们的研究结果为 HCV 对 III 型 IFN 反应的控制提供了重要证据，并进一步阐明了 HCV 感染持续存在的分子机制。
