title: Impaired cytokine response in myeloid dendritic cells in chronic hepatitis C virus infection regardless of enhanced expression of Toll-like receptors and retinoic acid inducible gene-I.
abstract: Dendritic cells utilize various sets of Toll-like receptors (TLR) or cytosolic sensors to detect pathogens and evoke immune responses. In patients with hepatitis C virus (HCV) infection, a higher prevalence of various infectious diseases is reported; suggesting that innate immunity against pathogens is impaired. The aim of this study was to clarify whether the TLR and retinoic acid inducible gene-I (RIG-I) system in myeloid dendritic cells is preserved or not in chronic HCV infection. The expression of TLRs, RIG-I and its relatives were compared in myeloid dendritic cells between 39 patients and 52 healthy volunteers. The induction of type-I interferon (IFN) and inflammatory cytokines was examined in response to agonists for TLR2 (palmitoyl-3-cysteine-serine-lysine-4), TLR3/RIG-I (polyinosine-polycytidylic acid) or TLR4 (lipopolysaccharide). The relative expressions of TLR2, TLR4, RIG-I, and LGP2 from the patients were significantly higher than those from the volunteers, whereas TLR3 and MDA-5 expressions did not differ. In search for factors regulating TLR/RIG-I expression, it was shown that IFN-alpha, polyinosine-polycytidylic acid and lipopolysaccharide induced TLR3, TLR4 and RIG-I, but TNF-alpha, HCV core or HCV non-structural proteins did not. For the functional analyses, myeloid dendritic cells from the patients induced significantly less amounts of IFN-beta, TNF-alpha and IL-12p70 in response to polyinosine-polycytidylic acid or lipopolysaccharide. It is noteworthy that the expression of TRIF and TRAF6, which are essential adaptor molecules transmitting TLR3 or TLR4-dependent signals, is reduced in the patients. Thus, innate cytokine responses in myeloid dendritic cells are impaired regardless of enhanced expressions of TLR2, TLR4, and RIG-I in HCV infection.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Michiyo
authors.initials: M
authors.lastname: Inoue
authors.forename: Ichiyo
authors.initials: I
authors.lastname: Itose
authors.forename: Hideki
authors.initials: H
authors.lastname: Miyatake
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sakakibara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yakushijin
authors.forename: Naruyasu
authors.initials: N
authors.lastname: Kakita
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Akinori
authors.initials: A
authors.lastname: Kasahara
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D016898:Interferon-alpha; C431552:RAI1 protein, human; C470409:TICAM1 protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D011070:Poly I-C