title: Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus.
abstract: BACKGROUND
  Specific differences in signaling and antiviral properties between the different Lambda-interferons, a novel group of interferons composed of IL-28A, IL-28B and IL-29, are currently unknown. This is the first study comparatively investigating the transcriptome and the antiviral properties of the Lambda-interferons IL-28A and IL-29.
  
  
  RESULTS
  Expression studies were performed by microarray analysis, quantitative PCR (qPCR), reporter gene assays and immunoluminometric assays. Signaling was analyzed by Western blot. HCV replication was measured in Huh-7 cells expressing subgenomic HCV replicon. All hepatic cell lines investigated as well as primary hepatocytes expressed both IFN-λ receptor subunits IL-10R2 and IFN-λR1. Both, IL-28A and IL-29 activated STAT1 signaling. As revealed by microarray analysis, similar genes were induced by both cytokines in Huh-7 cells (IL-28A: 117 genes; IL-29: 111 genes), many of them playing a role in antiviral immunity. However, only IL-28A was able to significantly down-regulate gene expression (n = 272 down-regulated genes). Both cytokines significantly decreased HCV replication in Huh-7 cells. In comparison to liver biopsies of patients with non-viral liver disease, liver biopsies of patients with HCV showed significantly increased mRNA expression of IL-28A and IL-29. Moreover, IL-28A serum protein levels were elevated in HCV patients. In a murine model of viral hepatitis, IL-28 expression was significantly increased.
  
  
  CONCLUSIONS
  IL-28A and IL-29 are up-regulated in HCV patients and are similarly effective in inducing antiviral genes and inhibiting HCV replication. In contrast to IL-29, IL-28A is a potent gene repressor. Both IFN-λs may have therapeutic potential in the treatment of chronic HCV.
authors.affiliation: Department of Medicine II, University Hospital Munich-Grosshadern, University of Munich, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Diegelmann
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zitzmann
authors.forename: Artur
authors.initials: A
authors.lastname: Kaul
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Helmut M
authors.initials: HM
authors.lastname: Diepolder
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000378:metabolism; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000737:chemistry* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008099:Liver / Q000378:metabolism; D051379:Mice; D018146:Muromegalovirus / Q000235:genetics; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; D050796:STAT3 Transcription Factor; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494086:STAT3 protein, human