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Transcriptional regulation of IFN- λ genes in Hepatitis C virus-infected hepatocytes via IRF-3 · IRF-7 · NF- κ B complex

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TLR3, 7, 8, and 9 induce human IFN-λ gene expression in human primary hepatocytes. Human primary hepatocytes were incubated with JFH-1, Pam3CSK4 (1 μg/ml), HKLM (108 cells/ml), Poly (I-C) (5 μg/ml), LPS (10 μg/ml), Flagellin (1 μg/ml), FSL-1 (100 ng/ml), Imiquimod (1 μg/ml), ssRNA (1 μg/ml), or ODN2006 (5μM) for 24 hours. (A) Toll-like receptors (TLR) and their respective ligands. Supernatants were harvested and IL-28B (B) and IL-29 (C) were measured by ELISA. Data are the mean ± SD of triplicate data points from one experiment. Results are representative of three independent experiments. Statistical significance (p<0.01) is relative to JFH-1 infection.
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Figure 8: TLR3, 7, 8, and 9 induce human IFN-λ gene expression in human primary hepatocytes. Human primary hepatocytes were incubated with JFH-1, Pam3CSK4 (1 μg/ml), HKLM (108 cells/ml), Poly (I-C) (5 μg/ml), LPS (10 μg/ml), Flagellin (1 μg/ml), FSL-1 (100 ng/ml), Imiquimod (1 μg/ml), ssRNA (1 μg/ml), or ODN2006 (5μM) for 24 hours. (A) Toll-like receptors (TLR) and their respective ligands. Supernatants were harvested and IL-28B (B) and IL-29 (C) were measured by ELISA. Data are the mean ± SD of triplicate data points from one experiment. Results are representative of three independent experiments. Statistical significance (p<0.01) is relative to JFH-1 infection.

Mentions: 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 (Figure 1). 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, andIL-29 genes is localized to a 1-kb region in their respective promoters (Figure 2, 4). Notably, interferon regulatory factor (IRF)-3 and -7 are the key transcriptional factors for the induction of IL-28A and IL-28Bgenes (Figure 5, 6), whereas NF-κB is an additional requirement for the induction of the IL-29 gene (Figure 3). 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 (Figure 8). 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) (Figure 7), suggesting that such combinatorial therapies may be beneficial for the treatment of chronic HCV infection.


Transcriptional regulation of IFN- λ genes in Hepatitis C virus-infected hepatocytes via IRF-3 · IRF-7 · NF- κ B complex
TLR3, 7, 8, and 9 induce human IFN-λ gene expression in human primary hepatocytes. Human primary hepatocytes were incubated with JFH-1, Pam3CSK4 (1 μg/ml), HKLM (108 cells/ml), Poly (I-C) (5 μg/ml), LPS (10 μg/ml), Flagellin (1 μg/ml), FSL-1 (100 ng/ml), Imiquimod (1 μg/ml), ssRNA (1 μg/ml), or ODN2006 (5μM) for 24 hours. (A) Toll-like receptors (TLR) and their respective ligands. Supernatants were harvested and IL-28B (B) and IL-29 (C) were measured by ELISA. Data are the mean ± SD of triplicate data points from one experiment. Results are representative of three independent experiments. Statistical significance (p<0.01) is relative to JFH-1 infection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4288562&req=5

Figure 8: TLR3, 7, 8, and 9 induce human IFN-λ gene expression in human primary hepatocytes. Human primary hepatocytes were incubated with JFH-1, Pam3CSK4 (1 μg/ml), HKLM (108 cells/ml), Poly (I-C) (5 μg/ml), LPS (10 μg/ml), Flagellin (1 μg/ml), FSL-1 (100 ng/ml), Imiquimod (1 μg/ml), ssRNA (1 μg/ml), or ODN2006 (5μM) for 24 hours. (A) Toll-like receptors (TLR) and their respective ligands. Supernatants were harvested and IL-28B (B) and IL-29 (C) were measured by ELISA. Data are the mean ± SD of triplicate data points from one experiment. Results are representative of three independent experiments. Statistical significance (p<0.01) is relative to JFH-1 infection.
Mentions: 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 (Figure 1). 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, andIL-29 genes is localized to a 1-kb region in their respective promoters (Figure 2, 4). Notably, interferon regulatory factor (IRF)-3 and -7 are the key transcriptional factors for the induction of IL-28A and IL-28Bgenes (Figure 5, 6), whereas NF-κB is an additional requirement for the induction of the IL-29 gene (Figure 3). 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 (Figure 8). 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) (Figure 7), suggesting that such combinatorial therapies may be beneficial for the treatment of chronic HCV infection.

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No MeSH data available.


Related in: MedlinePlus