Retinoic acid inducible gene-I (RIG-I) signaling of hepatic stellate cells inhibits hepatitis C virus replication in hepatocytes.
Retinoic acid inducible gene-I (RIG-I) is critical in the activation of the type I IFN-dependent antiviral innate immune response to hepatitis C virus (HCV) infection. We examined whether hepatic stellate cells (HSC; LX-2) possess a functional RIG-I signaling pathway and produce antiviral factors that can inhibit HCV. We showed that LX-2 cells treated with the RIG-I ligand (5'ppp-dsRNA) expressed significantly higher levels of IFN-β and IFN-λ than the control cells. The RIG-I activation in LX-2 cells also induced the expression of Toll-like receptor 3 (TLR3) and IFN regulatory factor-7 (IRF-7), the key regulators of the IFN signaling pathway. When HCV Japanese fulminant hepatitis (JFH)-1-infected hepatocytes were co-cultured with LX-2 cells stimulated with 5'ppp-dsRNA or incubated in media conditioned with supernatant (SN) from 5'ppp-dsRNA-stimulated LX-2 cells, HCV replication in hepatocytes was suppressed significantly. This LX-2 cell action on HCV replication was mediated through both IFN-β and IFN-λ, as Abs to IFN-α/β or IFN-λ receptors could neutralize the LX-2 SN-mediated anti-HCV effect. The role of IFNs in LX-2 cell-mediated anti-HCV activity is further supported by the observation that LX-2 SN treatment induced the expression of IFN stimulated genes, 2'-5'-oligoadenylate synthase-1 (OAS-1) and myxovirus resistance A (MxA), in HCV-infected Huh7 cells. These observations highlight the importance of HSC in liver innate immunity against HCV infection via a RIG-I-mediated signaling pathway.
The Center for Animal Experiment and ABSL-3 Laboratory, Wuhan University, Wuhan, People's Republic of China.
Yizhong
Y
Wang
Li
L
Ye
Xu
X
Wang
Jieliang
J
Li
Li
L
Song
Wenzhe
W
Ho
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D019138:Antibodies, Blocking / Q000494:pharmacology; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000276:immunology; D006526:Hepatitis C / Q000188:drug therapy* / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D064547:Myxovirus Resistance Proteins; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D000095022:Interferon Lambda
D015088:2',5'-Oligoadenylate Synthetase; D019138:Antibodies, Blocking; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D019204:GTP-Binding Proteins; D050839:Interferon Regulatory Factor-7; D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; D064547:Myxovirus Resistance Proteins; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579071:MX1 protein, human; C495344:TLR3 protein, human; C452820:RIGI protein, human