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.

Abstract

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.

• Authors: Bing Liu, Shan Chen, Yujuan Guan, Limin Chen
• Journal: PloS one (PLoS One) Vol. 10 Issue 7 Pg. e0133800 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26193702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• interferon-lambda, human
• Interferon-alpha
• Interleukins
• SOCS1 protein, human
• STAT1 Transcription Factor
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins
• Interferons
• Janus Kinases

Topics

• Antiviral Agents (pharmacology)
• Blotting, Western
• Carcinoma, Hepatocellular (genetics, metabolism, virology)
• Cell Line, Tumor
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hepacivirus (drug effects, physiology)
• Hepatitis C (drug therapy, virology)
• Host-Pathogen Interactions (drug effects)
• Humans
• Interferon-alpha (pharmacology)
• Interferons (pharmacology)
• Interleukins (pharmacology)
• Janus Kinases (metabolism)
• Middle Aged
• Phosphorylation (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT1 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins (genetics, metabolism)
• Time Factors