Type III Interferon Induces Distinct SOCS1 Expression Pattern that Contributes to Delayed but Prolonged Activation of Jak/STAT Signaling Pathway: Implications for Treatment Non-Response in HCV Patients

Suppressor of cytokine signaling 1 (SOCS1) has long been thought to block type I interferon signaling. However, IFN-λ, a type III IFN with limited receptor expression in hepatic cells, efficiently inhibits HCV (Hepatitis C virus) replication in vivo with potentially less side effects than IFN-α. Previous studies demonstrated that type I and type III activated Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway differently, with delayed but prolonged activation by IFN-λ stimulation compared to IFNα/β. However, the molecular mechanisms underlying this observation is not well understood. Here, we found that there are distinct differences in SOCS1 expression patterns in Huh-7.5.1 cells following stimulation with IFN-α and IFN-λ. IFN-λ induced a faster but shorter expression of SOCS1. Furthermore, we confirmed that SOCS1 over-expression abrogates anti-HCV effect of both IFN-α and IFN-λ, leading to increased HCV RNA replication in both HCV replicon cells and JFH1 HCV culture system. In line with this, SOCS1 over-expression inhibited STAT1 phosphorylation, attenuated IFN-stimulated response elements (ISRE) reporter activity, and blocked IFN-stimulated genes (ISGs) expression. Finally, we measured SOCS1 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) with or without IFN-α treatment from 48 chronic hepatitis C patients and we found the baseline SOCS1 expression levels are higher in treatment non-responders than in responders before IFN-α treatment. Taken together, SOCS1 acts as a suppressor for both type I and type III IFNs and is negatively associated with sustained virological response (SVR) to IFN-based therapy in patients with HCV. More importantly, faster but shorter induction of SOCS1 by IFN-λ may contribute to delayed but prolonged activation of IFN signaling and ISG expression kinetics by type III IFN.

细胞因子信号转导抑制因子1（Suppressor of cytokine signaling 1, SOCS1）长期以来被认为可阻断I型干扰素信号通路。然而，干扰素λ（IFN-λ，一种III型干扰素，其受体在肝细胞中表达有限）可在体内有效抑制丙型肝炎病毒（Hepatitis C virus, HCV）的复制，且相较于干扰素α（IFN-α）具有更低的潜在不良反应。既往研究表明，I型与III型干扰素对贾纳斯激酶/信号转导与转录激活因子（Janus kinase/signal transducer and activator of transcription, Jak/STAT）信号通路的激活模式存在差异：相较于IFN-α/β，IFN-λ刺激后的通路激活更为迟缓但持续时间更长。然而，该现象背后的分子机制尚未得到充分阐明。本研究发现，在经IFN-α与IFN-λ分别刺激后，Huh-7.5.1细胞中的SOCS1表达模式存在显著差异：IFN-λ可诱导SOCS1更快表达，但表达持续时间更短。此外，我们证实，SOCS1过表达可抵消IFN-α与IFN-λ的抗HCV效应，导致HCV复制子细胞及JFH1型HCV培养体系中的HCV RNA复制水平均升高。与此一致的是，SOCS1过表达可抑制STAT1磷酸化、减弱干扰素刺激应答元件（IFN-stimulated response elements, ISRE）的报告基因活性，并阻断干扰素刺激基因（IFN-stimulated genes, ISGs）的表达。最后，我们对48名慢性丙型肝炎患者接受或未接受IFN-α治疗后的外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）中SOCS1 mRNA的表达水平进行了检测，结果发现，在IFN-α治疗前，治疗无应答者的基线SOCS1表达水平高于应答者。综上，SOCS1可同时作为I型与III型干扰素的抑制因子，且与HCV患者接受干扰素治疗后的持续病毒学应答（sustained virological response, SVR）呈负相关。更重要的是，IFN-λ诱导SOCS1的速度更快但持续时间更短，这可能是III型干扰素导致的干扰素信号通路及ISG表达动力学呈现迟缓但持久激活状态的原因。