title: Hepatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-α responses.
abstract: TNF-α is a proinflammatory cytokine, dramatically elevated during pathogenic infection and often responsible for inflammation-induced disease pathology. SOCS proteins are inhibitors of cytokine signaling and regulators of inflammation. In this study, we found that both SOCS1 and SOCS3 were transiently induced by TNF-α and negatively regulate its NF-κB-mediated signal transduction. We discovered that PBMCs from HCV-infected patients have elevated endogenous SOCS3 expression but less TNF-α-mediated IκB degradation and proinflammatory cytokine production than healthy controls. HCV protein expression in Huh7 hepatocytes also induced SOCS3 and directly inhibited TNF-α-mediated IL-8 production. Furthermore, we found that SOCS3 associates with TRAF2 and inhibits TRAF2-mediated NF-κB promoter activity, suggesting a mechanism by which SOCS3 inhibits TNF-α-mediated signaling. These results demonstrate a role for SOCS3 in regulating proinflammatory TNF-α signal transduction and reveal a novel immune-modulatory mechanism by which HCV suppresses inflammatory responses in primary immune cells and hepatocytes, perhaps explaining mild pathology often associated with acute HCV infection.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, and.
authors.forename: Aideen S
authors.initials: AS
authors.lastname: Collins
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, and.
authors.forename: Suaad
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Napoletano
authors.affiliation: Institute of Immunology, National University of Ireland, Maynooth, Ireland;
authors.forename: Martina
authors.initials: M
authors.lastname: Schroeder
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Science, Queen's University of Belfast, Northern Ireland; and.
authors.forename: James A
authors.initials: JA
authors.lastname: Johnston
authors.affiliation: National Liver Transplant Unit, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: John E
authors.initials: JE
authors.lastname: Hegarty
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, and School of Medicine, Trinity College Dublin, Ireland;
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, and n.stevenson@tcd.ie.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Stevenson
mesh_terms: D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016209:Interleukin-8 / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D016328:NF-kappa B; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha
keywords: hepatocytes; inflammation; peripheral blood mononuclear cells; signal transduction; viral infection