Abstract
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 IL-28A, IL-28B, and IL-29 genes is localized to a 1-kb 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, whereas 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 TLR pathways in IFN-λ production. Furthermore, the addition of IFN-λ to HCV-infected hepatocytes decreased viral replication and produced a concurrent reduction in microRNA-122 (miR-122). The decrease in viral replication was enhanced by the co-administration of IFN-λ and miR-122 inhibitor (miRIDIAN), suggesting that such combinatorial therapies may be beneficial for the treatment of chronic HCV infection.
Highlights
IFN- gene induction in hepatitis C virus infected hepatocytes is not well defined
We identified the involvement of proximal regions of the IFN- promoter in Hepatitis C virus (HCV)-induced expression of IFN- genes in hepatocytes and demonstrated that interferon regulatory factor (IRF)-31⁄7IRF-7 are required for IL-28A and IL-28B gene expression, whereas IL-29 gene induction requires NF-B in addition to IRF31⁄7IRF-7
Using human primary hepatocytes and the human hepatocyte cell line PH5CH8, we first determined that HCV infection and poly(I:C) stimulation are capable of inducing IL-28A, IL-28B, and IL-29 genes and the production of their proteins
Summary
IFN- gene induction in hepatitis C virus infected hepatocytes is not well defined. Results: IRF-3, IRF-7, and NF-B transcribe type III IFNs. Hepatitis C virus (HCV) infection in hepatocytes stimulates innate antiviral responses including the production of type III interferons (IFN-), including IL-28A, IL-28B, and IL-29. The molecular mechanisms for HCV-mediated induction of IFN- genes have not been well defined in hepatocytes To this end, we found that HCV or poly(I:C), which mimics intracellular viral RNA, induced transcription of IFN- genes in human hepatoma cells and primary human hepatocytes. Co-treatment with IFN- and miR-122 inhibitor (miRIDIAN) resulted in a more pronounced suppression of HCV when compared with treatment with IFN- alone These observations affirm the antiviral effects of IFN- and miR-122 inhibitors and suggest their use as potential alternatives to the current treatment for HCV infection
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