Z Gastroenterol 2010; 48 - P456
DOI: 10.1055/s-0030-1263896

Analysis of the antiviral efficacy and target genes of the Lambda-interferons IL-28A and IL-29

J Diegelmann 1, CJ Auernhammer 1, B Göke 1, H Diepolder 1, S Brand 1
  • 1Universitätsklinikum München-Großhadern, Medizinische Klinik II, München, Germany

Background & Aims: 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. Several recent publications describe an association between single nucleotide polymorphisms in the IL28B gene region and the clearance of HCV infection. This is the first study comparatively investigating the transcriptome and the antiviral properties of the Lambda-interferons IL-29 and IL-28A, which is on an mRNA level 98% identical to IL-28B.

Methods: 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.

Results: All hepatic cell lines investigated as well as primary hepatocytes expressed both IFN-λ receptor subunits IL-10R2 and IL-28R. 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 also significantly increased.

Conclusion: 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.