Correlation between the suppressor of cytokine signaling-1 and 3 and hepatitis B virus: possible roles in the resistance to interferon treatment

Ling-Yao Du,Li Liu,En-Qiang Chen,Xing Cheng,Yao-Li Cui,Hong Tang

doi:10.1186/1743-422x-11-51

Abstract

BackgroundThe suppressor of cytokine signaling family (SOCS) is an important negative regulator in the JAK-STAT signaling pathway. This study was designed to explore the correlation between SOCS-1, 2 and 3, Hepatitis B Virus (HBV) and interferon (IFN), and the relationship between SOCS and IFN therapeutic efficacy.MethodsFour types of mouse models were established. Mice were administered with HBV replicative plasmid pHBV4.1 and IFN inducer Poly IC (Group A), pHBV4.1 (Group B), Poly IC (Group C) and saline (Group D), respectively. Liver tissues were harvested from the mice and SOCS expression was determined. Meanwhile, patients with chronic hepatitis B (CHB) were treated with pegylated interferon α-2b for 24-48 weeks. Liver biopsy was collected and the baseline SOCS expression was determined. Serum assay was performed for efficacy evaluation and correlation analysis.ResultsIn animal studies, the expression level of SOCS-1 and 3 was found in the descending order of B, A, C and D. The difference between Group B and D suggested that HBV could induce SOCS. The difference between Group A and C suggested that HBV could still induce SOCS with up-regulated endogenous IFN. The difference between Group C and D suggested that ploy IC could induce SOCS, while the difference between Group B and A suggested that Poly IC might have a stronger inhibition effect for SOCS. There was no difference in SOCS-2 expression. In clinical studies, eight of twenty-four enrolled patients achieved either complete or partial therapeutic response. The expression of both SOCS-1 and 3 was higher in CHB patients than in normal controls. The baseline HBV-DNA level was positively correlated with SOCS-1 and 3. The age, viral genotype, HBVDNA, SOCS-1 and SOCS-3 were found to be related to IFN efficacy.ConclusionHBV could induce both SOCS-1 and 3 expression regardless of endogenous IFN level. Elevated IFN could directly up-regulate SOCS-1 and 3 expression, but it could also indirectly down-regulate SOCS-1 and 3 expression by inhibiting HBV replication. HBV might play a more important role in the SOCS up-regulation than IFN, a possible reason why patients with high HBV viral load encounter poor efficacy of IFN treatment.

Highlights

The suppressor of cytokine signaling family (SOCS) is an important negative regulator in the JAK-STAT signaling pathway
It has been demonstrated that SOCS protein could inhibit the activity of JAKs and compete with STAT2 to bind to the phosphorylated tyrosine residues in cytokine receptors through its Src Homology 2 (SH2) domain
Animal studies Expression of SOCS-1 in liver tissues In this study, four groups of mice were administered with Hepatitis B Virus (HBV) replicative plasmid pHBV4.1 followed with IFN inducer Poly IC (Group A), pHBV4.1 (Group B), Poly IC (Group C) and saline (Group D), respectively

Summary

Introduction

The suppressor of cytokine signaling family (SOCS) is an important negative regulator in the JAK-STAT signaling pathway. Eight members of the SOCS family have been found, which include SOCS 1-7 and cytokine inducible Src Homology 2 (SH2) containing protein (CIS). They all consist of an amino-terminus, a SH2 domain in the middle, and a SOCS box in carboxy-terminus [9,10,11]. It has been demonstrated that SOCS protein could inhibit the activity of JAKs and compete with STAT2 to bind to the phosphorylated tyrosine residues in cytokine receptors through its SH2 domain. SOCS protein could mediate the degradation pathways of the activated signaling proteins or bind to the cytoplasmic protein tyrosine phosphatase SHP2, inhibiting the signal transduction [12]

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