title: Hepatitis C virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon and interleukin-6.
abstract: Hepatitis C virus (HCV) induces inflammatory signals, leading to hepatitis, hepatocellular carcinomas, and lymphomas. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized. In this study, we analyzed expression and regulation of the entire panel of toll-like receptors (TLRs) in human B cells following HCV infection in vitro. Among all of the TLRs (TLRs 1 to 10) examined, only TLR4 showed an altered expression (a three- to sevenfold up-regulation) after HCV infection. Peripheral blood mononuclear cells from HCV-infected individuals also showed a higher expression level of TLR4 compared with those of healthy individuals. HCV infection significantly increased beta interferon (IFN-beta) and interleukin-6 (IL-6) secretion from B cells, particularly after lipopolysaccharide stimulation. The increased IFN-beta and IL-6 production was mediated by TLR4 induction, since the introduction of the small interfering RNA against TLR4 specifically inhibited the HCV-induced cytokine production. Among all of the viral proteins, only NS5A caused TLR4 induction in hepatocytes and B cells. NS5A specifically activated the promoter of the TLR4 gene in both hepatocytes and B cells. In conclusion, HCV infection directly induces TLR4 expression and thereby activates B cells, which may contribute to the host's innate immune responses.
authors.affiliation: Department of Molecular Microbiology and Immunology, USC Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Kevin T H
authors.initials: KT
authors.lastname: Cheng
authors.forename: Vicky M-H
authors.initials: VM
authors.lastname: Sung
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Levine
authors.forename: Steven
authors.initials: S
authors.lastname: Foung
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000737:chemistry / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear; D011401:Promoter Regions, Genetic; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000276:immunology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D016899:Interferon-beta; D015850:Interleukin-6; D051197:Toll-Like Receptor 4; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase