Abstract
Hepatitis C virus (HCV) is a major cause of liver disease. The innate immune system is essential for controlling HCV replication, and HCV is recognized by RIG-I and TLR3, which evoke innate immune responses through IPS-1 and TICAM-1 adaptor molecules, respectively. IL-28B is a type III IFN, and genetic polymorphisms upstream of its gene are strongly associated with the efficacy of polyethylene glycol-IFN and ribavirin therapy. As seen with type I IFNs, type III IFNs induce antiviral responses to HCV. Recent studies established the essential role of TLR3-TICAM-1 pathway in type III IFN production in response to HCV infection. Contrary to previous studies, we revealed an essential role of IPS-1 in type III IFN production in response to HCV. First, using IPS-1 knockout mice, we revealed that IPS-1 was essential for type III IFN production by mouse hepatocytes and CD8(+) dendritic cells (DCs) in response to cytoplasmic HCV RNA. Second, we demonstrated that type III IFN induced RIG-I but not TLR3 expression in CD8(+) DCs and augmented type III IFN production in response to cytoplasmic HCV RNA. Moreover, we showed that type III IFN induced cytoplasmic antiviral protein expression in DCs and hepatocytes but failed to promote DC-mediated NK cell activation or cross-priming. Our study indicated that IPS-1-dependent pathway plays a crucial role in type III IFN production by CD8(+) DCs and hepatocytes in response to HCV, leading to cytoplasmic antiviral protein expressions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology*
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / immunology
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Adaptor Proteins, Vesicular Transport / metabolism
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Animals
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CD8 Antigens / immunology
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CD8 Antigens / metabolism
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Cell Line
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Cells, Cultured
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Cytokines / genetics
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Cytokines / immunology*
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Cytokines / metabolism
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DEAD Box Protein 58
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / immunology
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DEAD-box RNA Helicases / metabolism
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / virology
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Flow Cytometry
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Gene Expression / drug effects
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Gene Expression / immunology
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Hepacivirus / genetics
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Hepacivirus / immunology*
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Hepacivirus / physiology
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Hepatitis C / genetics
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Hepatitis C / immunology*
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Hepatitis C / metabolism
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Hepatocytes / immunology*
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Hepatocytes / metabolism
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Hepatocytes / virology
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Host-Pathogen Interactions / immunology
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Poly I-C / immunology
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Poly I-C / pharmacology
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RNA, Viral / genetics
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RNA, Viral / immunology
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RNA, Viral / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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CD8 Antigens
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Cytokines
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IPS-1 protein, mouse
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RNA, Viral
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TICAM-1 protein, mouse
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interferon-lambda protein, mouse
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Ddx58 protein, mouse
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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Poly I-C