caa a22 4500 445795832 CHVBK 20180317145124.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s10620-010-1395-y doi (NATIONALLICENCE)springer-10.1007/s10620-010-1395-y HCV-Related Proteins Activate Kupffer Cells Isolated from Human Liver Tissues [Elektronische Daten] [Naohiro Hosomura, Hiroshi Kono, Masato Tsuchiya, Kenichi Ishii, Masahito Ogiku, Masanori Matsuda, Hideki Fujii] Purpose: 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. Springer Science+Business Media, LLC, 2010 TNF-α nationallicence Toll-like receptor nationallicence Hydrogen peroxide nationallicence Inflammatory cytokine nationallicence DMSO : Dimethyl sulfoxide nationallicence ELISA : Enzyme-linked immunosorbent assay nationallicence HCC : Hepatocellular carcinoma nationallicence HCV : Hepatitis C virus nationallicence ICAM-1 : Intercellular adhesion molecule-1 nationallicence IL : Interleukin nationallicence KC : Kupffer cell nationallicence LPS : Lipopolysaccharide nationallicence MIP : Macrophage inflammatory protein nationallicence NS3 : Nonstructural 3 protein nationallicence NS4 : Nonstructural 4 protein nationallicence NS5 : Nonstructural 5 protein nationallicence t-BOOH : t-Butyl hydroperoxide nationallicence TLR : Toll-like receptor nationallicence TNF : Tumor necrosis factor nationallicence Hosomura Naohiro First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut Kono Hiroshi First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut Tsuchiya Masato First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut Ishii Kenichi First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut Ogiku Masahito First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut Matsuda Masanori First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut Fujii Hideki First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/4(2011-04-01), 1057-1064 0163-2116 56:4<1057 2011 56 10620 https://doi.org/10.1007/s10620-010-1395-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10620-010-1395-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hosomura Naohiro First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut NATIONALLICENCE 700 1- Kono Hiroshi First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut NATIONALLICENCE 700 1- Tsuchiya Masato First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut NATIONALLICENCE 700 1- Ishii Kenichi First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut NATIONALLICENCE 700 1- Ogiku Masahito First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut NATIONALLICENCE 700 1- Matsuda Masanori First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut NATIONALLICENCE 700 1- Fujii Hideki First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898, Chuo, Yamanashi, Japan aut NATIONALLICENCE 773 0- Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/4(2011-04-01), 1057-1064 0163-2116 56:4<1057 2011 56 10620 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer