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 PatientsReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

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.



Author: Bing Liu, Shan Chen, Yujuan Guan, Limin Chen

Source: http://plos.srce.hr/



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