Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
J Immunol. 2014 Mar 15;192(6):2770-7. doi: 10.4049/jimmunol.1301459. Epub 2014 Feb 14.
Hepatitis C virus (HCV) is a major cause of liver disease. The innate immune system is essential for controlling HCV replication, and HCV is recognized by RIG-I and TLR3, which evoke innate immune responses through IPS-1 and TICAM-1 adaptor molecules, respectively. IL-28B is a type III IFN, and genetic polymorphisms upstream of its gene are strongly associated with the efficacy of polyethylene glycol-IFN and ribavirin therapy. As seen with type I IFNs, type III IFNs induce antiviral responses to HCV. Recent studies established the essential role of TLR3-TICAM-1 pathway in type III IFN production in response to HCV infection. Contrary to previous studies, we revealed an essential role of IPS-1 in type III IFN production in response to HCV. First, using IPS-1 knockout mice, we revealed that IPS-1 was essential for type III IFN production by mouse hepatocytes and CD8(+) dendritic cells (DCs) in response to cytoplasmic HCV RNA. Second, we demonstrated that type III IFN induced RIG-I but not TLR3 expression in CD8(+) DCs and augmented type III IFN production in response to cytoplasmic HCV RNA. Moreover, we showed that type III IFN induced cytoplasmic antiviral protein expression in DCs and hepatocytes but failed to promote DC-mediated NK cell activation or cross-priming. Our study indicated that IPS-1-dependent pathway plays a crucial role in type III IFN production by CD8(+) DCs and hepatocytes in response to HCV, leading to cytoplasmic antiviral protein expressions.
丙型肝炎病毒 (HCV) 是肝脏疾病的主要病因。先天免疫系统对于控制 HCV 复制至关重要，HCV 被 RIG-I 和 TLR3 识别，这两种模式识别受体分别通过 IPS-1 和 TICAM-1 衔接分子引发先天免疫反应。IL-28B 是一种 III 型干扰素，其基因上游的遗传多态性与聚乙二醇干扰素和利巴韦林治疗的疗效密切相关。与 I 型干扰素一样，III 型干扰素诱导针对 HCV 的抗病毒反应。最近的研究确立了 TLR3-TICAM-1 途径在 HCV 感染后 III 型 IFN 产生中的重要作用。与先前的研究相反，我们揭示了 IPS-1 在 HCV 感染后 III 型 IFN 产生中的重要作用。首先，我们使用 IPS-1 敲除小鼠揭示了 IPS-1 对于鼠肝细胞和 CD8(+)树突状细胞 (DC) 对细胞质 HCV RNA 的反应中 III 型 IFN 产生是必需的。其次，我们证明 III 型 IFN 在 CD8(+) DC 中诱导 RIG-I 但不诱导 TLR3 的表达，并增强对细胞质 HCV RNA 的 III 型 IFN 产生。此外，我们表明 III 型 IFN 在 DC 和肝细胞中诱导细胞质抗病毒蛋白表达，但未能促进 DC 介导的 NK 细胞激活或交叉呈递。我们的研究表明 IPS-1 依赖性途径在 CD8(+) DC 和肝细胞对 HCV 的反应中对于 III 型 IFN 的产生起着至关重要的作用，导致细胞质抗病毒蛋白的表达。
