title: SOCS-1 inhibits expression of the antiviral proteins 2',5'-OAS and MxA induced by the novel interferon-lambdas IL-28A and IL-29.
abstract: Recently, we have shown that SOCS-1/3 overexpression in hepatic cells abrogates signaling of type I interferons (IFN) which may contribute to the frequently observed IFN resistance of hepatitis C virus (HCV). IFN-lambdas (IL-28A/B and IL-29), a novel group of IFNs, also efficiently inhibit HCV replication in vitro with potentially less hematopoietic side effects than IFN-alpha because of limited receptor expression in hematopoietic cells. To further evaluate the potential of IFN-lambdas in chronic viral hepatitis, we examined the influence of SOCS protein expression on IFN-lambda signaling. First, we show that hepatic cell lines express the IFN-lambda receptor complex consisting of IFN-lambdaR1 (IL-28R1) and IL-10R2. Whereas in mock-transfected HepG2 cells, IL-28A and IL-29 induced STAT1 and STAT3 phosphorylation, overexpression of SOCS-1 completely abrogated IL-28A and IL-29-induced STAT1/3 phosphorylation. Similarly, IL-28A and IL-29 induced mRNA expression of the antiviral proteins 2',5'-OAS and MxA was abolished by overexpression of SOCS-1. In conclusion, we assume that despite antiviral properties of IFN-lambdas, their efficacy as antiviral agents may have similar limitations as IFN-alpha due to inhibition by SOCS proteins.
authors.affiliation: Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany. stepha.brand@med.uni-muenchen.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zitzmann
authors.forename: Julia
authors.initials: J
authors.lastname: Dambacher
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: George
authors.initials: G
authors.lastname: Vlotides
authors.forename: Sören T
authors.initials: ST
authors.lastname: Eichhorst
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Helmut
authors.initials: H
authors.lastname: Diepolder
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines; D004268:DNA-Binding Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007372:Interferons / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D064547:Myxovirus Resistance Proteins; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D000095022:Interferon Lambda
chemical_list: D015088:2',5'-Oligoadenylate Synthetase; D000998:Antiviral Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D019204:GTP-Binding Proteins; D007372:Interferons; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D064547:Myxovirus Resistance Proteins; D019000:Phosphotyrosine; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579071:MX1 protein, human; C108944:SOCS1 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C475085:OAS1 protein, human