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.

Bing Liu,Yujuan Guan,Shan Chen,Limin Chen,Wenzhe Ho

doi:10.1371/journal.pone.0133800

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.

Highlights

An estimated of 130–170 million people are chronically infected with HCV worldwide, which is a growing global pandemic and financial burden to the society [1]
Having observed the different kinetic profiles of Suppressor of cytokine signaling 1 (SOCS1) expression stimulated by IFN-α and IFN-λ, we subsequently investigated the role of SOCS1 over-expression on the expression kinetics of IFN-stimulated genes (ISGs)
IFN-α activated IFN signaling resulting in the increased expression of ISGs faster but lasted shorter compared to IFN-λ, and SOCS1 over-expression significantly blunted the increases expression of interferon stimulated gene 15 (ISG15) following stimulation with IFN-α and IFN-λ (Fig 1B)

Summary

Introduction

An estimated of 130–170 million people are chronically infected with HCV worldwide, which is a growing global pandemic and financial burden to the society [1]. With successful development of direct acting antiviral antivirals (DAAs), SVR in HCV chronically infected patients has been increased tremendously [2,3,4]. It is essential to develop methods to predict treatment response and uncover mechanism of viral resistance to further increase SVR. In consideration of viral resistance and side effects due to the fact that virtually all cell types express type I IFN receptor [6], other types of interferons with better efficacy and less toxicity should be explored. IFN-λs, which trigger the overlapping Jak/STAT signaling pathway with IFN-α through distinct receptors expressed only in restricted cell types [7], is an ideal therapeutic candidate for HCV therapy. Recombinant IFN-λ is currently being tested in clinical trial with promising preliminary data [8,9,10]

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