Transcriptional regulation of IFN-{lambda} genes in hepatitis C virus-infected hepatocytes via IRF-3/IRF-7/NF-{kappa}B [Immunology]

January 2nd, 2014 by Lee, H.-C., Narayanan, S., Park, S.-J., Seong, S.-Y., Hahn, Y. S.

Hepatitis C virus (HCV) infection in hepatocytes stimulates innate antiviral responses including the production of type III interferons (IFN-λ), including IL-28A, IL-28B, and IL-29. However, the molecular mechanism(s) regulating the expression of IFN-λ genes in HCV-infected hepatocytes remains undefined. In this study, we examined regulatory elements involved in the induction of IFN-λ genes following HCV infection in hepatocytes and further determined the binding of specific transcription factor(s) to promoter regions of IFN-λ genes. Our studies reveal that the regulatory portion for IL28A, IL-28B, IL-29 genes is localized to a 1kb region in their respective promoters. Notably, interferon regulatory factor (IRF)-3 and -7 are the key transcriptional factors for the induction of IL-28A and IL-28B genes, while NF-κB is an additional requirement for the induction of the IL-29 gene. Ligation of toll-like receptors (TLR) 3, 7, 8, and 9, which also activate IRFs and NF-κB, resulted in more robust production of IFN-λ than that observed with HCV infection, verifying the importance of these TLR pathways in IFN-λ production. Furthermore, addition of IFN-λ to HCV-infected hepatocytes decreased viral replication and produced a concurrent reduction in miR-122. The decrease in viral replication was enhanced by the co-adminstration of IFN-λ and miR-122 inhibitor (miRIDIAN), suggesting that such combinatorial therapies may be beneficial for the treatment of chronic HCV infection.