title: TNF-α Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism.
abstract: Invasion by infectious pathogens can elicit a range of cytokine responses from host cells. These cytokines provide the initial host defense mechanism. In this report, we demonstrate that TNF-α, a pro-inflammatory cytokine, can be induced by hepatitis C virus (HCV) in its host cells in a biphasic manner. The initial induction of TNF-α by HCV was prompt and could be blocked by the antibody directed against the HCV E2 envelope protein and by chemicals that inhibit endocytosis, indicating the specificity of endocytic uptake of HCV in this induction. Further studies indicated that the induction of TNF-α was dependent on toll-like receptors 7 and 8 (TLR7/8) but not on other intracellular pattern recognition receptors. Consistently, siRNA-mediated gene silencing of the downstream effectors in the TLR7/8 signaling pathway including MyD88, IRAK1, TRAF6, TAK1 and p65 NF-κB suppressed the expression of TNF-α. The role of p65 NF-κB in the induction of TNF-α via transcriptional up-regulation was further confirmed by the chromatin immunoprecipitation assay. TNF-α induced by HCV could activate its own receptor TNFR1 on hepatocytes to suppress HCV replication. This suppressive effect of TNF-α on HCV was due to its role in supporting interferon signaling, as the suppression of its expression led to the loss of IFNAR2 and impaired interferon signaling and the induction of interferon-stimulated genes. In conclusion, our results indicate that hepatocytes can sense HCV infection via TLR7/8 to induce the expression of TNF-α, which inhibits HCV replication via an autocrine mechanism to support interferon signaling.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Stephanie Tze
authors.initials: ST
authors.lastname: Chan
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Ja Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cho
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Jing-hsiung James
authors.initials: JH
authors.lastname: Ou
mesh_terms: D017209:Apoptosis; D019898:Autocrine Communication; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C439524:TNF protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons