IPS-1 Is Essential for Type III IFN Production by Hepatocytes and Dendritic Cells in Response to Hepatitis C Virus Infection
IPS-1 Is Essential for Type III IFN Production by Hepatocytes and Dendritic Cells in Response to Hepatitis C Virus Infection
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DOI：
10.4049/jimmunol.1301459
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发表时间：
2014-03-15
影响因子：
4.4
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
--
作者：
Okamoto, Masaaki;Oshiumi, Hiroyuki;Seya, Tsukasa
丙型肝炎病毒（HCV）是肝脏疾病的主要原因。先天免疫系统对于控制HCV复制是必不可少的，并且HCV被RIG-I和TLR3识别，其分别通过IPS-1和TICAM-1衔接分子引起先天免疫应答。IL-28 B是一种III型IFN，其基因上游的遗传多态性与聚乙二醇-IFN和利巴韦林治疗的疗效密切相关。如I型IFN所见，III型IFN诱导对HCV的抗病毒应答。最近的研究确定了TLR3-TICAM-1通路在响应HCV感染的III型IFN产生中的重要作用。与以前的研究相反，我们揭示了IPS-1在响应HCV的III型IFN产生中的重要作用。首先，使用IPS-1敲除小鼠，我们发现IPS-1对于小鼠肝细胞和CD8（+）树突状细胞（DC）响应胞质HCV RNA产生III型IFN是必需的。第二，我们证明了III型IFN诱导RIG-I而非TLR3在CD8（+）DC中表达，并增强了III型IFN对细胞质HCV RNA的应答。此外，我们发现，III型IFN诱导细胞质抗病毒蛋白在DC和肝细胞中的表达，但未能促进DC介导的NK细胞活化或交叉引发。我们的研究表明，IPS-1依赖性途径在CD8（+）DC和肝细胞应答HCV产生III型IFN，导致胞浆抗病毒蛋白表达中起关键作用。
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.