Abstract
BackgroundSpecific 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.Methodology/Principal FindingsExpression 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/SignificanceIL-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.
Highlights
Several novel cytokines of the IL-10-like cytokine family have been discovered, including interferon (IFN)-ls [1,2]
Hepatic cells express the IFN-l receptor complex In order to utilize a hepatic cell model to study the IFN-l ligand-receptor system, we first confirmed that the IFN-l receptor subunits IL-10R2 and IFNl-R1 are present in hepatic cells
RTPCR analysis demonstrated IL-10R2 and IFNl-R1 mRNA expression in several human hepatic cancer derived cell lines (HepG2, Hep3B, Huh-7) as well as in hepatitis C virus (HCV) replicon expressing Huh-7 5-2 cells and Huh-7 cells cured from HCV by IFN-a and IFN-c (HCV-cured Huh-7) (Fig. 1A)
Summary
Several novel cytokines of the IL-10-like cytokine family have been discovered, including interferon (IFN)-ls [1,2]. IFN-ls are related to IL-10 and other members of the IL-10-like family such as IL-22 [3], which has recently shown to confer hepatoprotection [4,5]. 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
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