title: HCV-related proteins activate Kupffer cells isolated from human liver tissues.
abstract: OBJECTIVE
  It was reported from this laboratory that Kupffer cells (KCs) were activated in patients infected with HCV. Since dendritic cells, monocytes, and macrophages were activated by stimulation with HCV-related proteins, the specific aim of this study was to investigate the role of HCV-related proteins in activation of KCs, the signal pathway of activation of KCs mediated by Toll-like receptor (TLR) 4, and the influence of HCV infection on function of KCs.
  
  
  METHODS
  Kupffer cells isolated from non-cancerous surgical specimen were co-cultured with HCV-related proteins (Core, NS3, NS4, and NS5), and production of cytokines (TNF-α, IL-1β, and IL-10) and hydrogen peroxide were assessed. Furthermore, effects of neutralization antibodies against the TLR2, TLR3, or TLR4, and cytochalasin B on the production TNF-α by KCs were investigated.
  
  
  RESULTS
  Kupffer cells produced markedly a proinflammatory cytokine TNF-α by stimulation with all HCV-related proteins studied, and values were as same as production by KCs stimulated with LPS. Importantly, this production in the case of NS3 was significantly blunted by about 60% by neutralization antibodies against the TLR4, but not cytochalasin B. Production of TNF-α by isolated KCs stimulated with LPS was significantly greater in the HCV-infected livers than the HCV/HBV-negative livers.
  
  
  CONCLUSIONS
  These results indicated that HCV-related proteins may cause prolonged activation of KCs in the HCV-infected liver, leading to accumulation of inflammatory cytokines that contribute to DNA damage and carcinogenesis. Furthermore, function of KCs was difference between patients infected with and without HCV infection.
authors.affiliation: First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Hosomura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kono
authors.forename: Masato
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishii
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogiku
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsuda
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D000368:Aged; D057134:Antibodies, Neutralizing / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003571:Cytochalasin B / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D008297:Male; D008875:Middle Aged; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014764:Viral Proteins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D016753:Interleukin-10; D003571:Cytochalasin B; D006861:Hydrogen Peroxide