SOCS-1 and SOCS-3 inhibit IFN-α-induced expression of the antiviral proteins 2,5-OAS and MxA

Although the use of IFN-α in combination with ribavirin has improved the treatment efficacy of chronic hepatitis C virus (HCV) infection, 20–50% of patients still fail to eradicate the virus depending on the HCV genotype. Recently, overexpression of HCV core protein has been shown to inhibit IFN sig...

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Published in:Biochemical and biophysical research communications 2004-07, Vol.320 (3), p.1007-1014
Main Authors: Vlotides, George, Sörensen, Astrid S, Kopp, Florian, Zitzmann, Kathrin, Cengic, Neziha, Brand, Stephan, Zachoval, Reinhart, Auernhammer, Christoph J
Format: Article
Language:English
Subjects:
2 ′,5 ′-OAS
2',5'-Oligoadenylate Synthetase - metabolism
Antiviral Agents - metabolism
Carcinoma, Hepatocellular - metabolism
Carrier Proteins - metabolism
Cell Line, Tumor
GTP-Binding Proteins - metabolism
Hepatitis C virus
HepG2
Humans
IFN-α
Interferon-alpha - pharmacology
Intracellular Signaling Peptides and Proteins
Liver Neoplasms - metabolism
MxA
Myxovirus Resistance Proteins
Repressor Proteins - metabolism
SOCS
STAT
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins
Transcription Factors - metabolism
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Summary:Although the use of IFN-α in combination with ribavirin has improved the treatment efficacy of chronic hepatitis C virus (HCV) infection, 20–50% of patients still fail to eradicate the virus depending on the HCV genotype. Recently, overexpression of HCV core protein has been shown to inhibit IFN signaling and induce SOCS-3 expression. Aim of this study was to examine the putative role of SOCS proteins in IFN resistance. By Western blot analysis, a 4-fold induction of STAT-1/3 phosphorylation by IFN-α was observed in mock-transfected HepG2 clones. In contrast, IFN-induced STAT-1/3 phosphorylation was considerably downregulated by SOCS-1/3 overexpression. In mock-transfected cells, IFN-α induced 2 ′,5 ′-OAS and myxovirus resistance A (MxA) promoter activity 40- to 80-fold and 10- to 35-fold, respectively, and this effect was abrogated in SOCS-1/3 overexpressing cells. As detected by Northern blot technique, IFN-α potently induced 2 ′,5 ′-OAS and MxA mRNA expression in the control clones. Overexpression of SOCS-1 completely abolished both 2 ′,5 ′-OAS and MxA mRNA expression, whereas SOCS-3 mainly inhibited 2 ′,5 ′-OAS mRNA expression. Our results demonstrate that SOCS-1 and SOCS-3 proteins inhibit IFN-α-induced activation of the Jak–STAT pathway and expression of the antiviral proteins 2 ′,5 ′-OAS and MxA. These data suggest a potential role of SOCS proteins in IFN resistance during antiviral treatment.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2004.06.051