HCV-Related Proteins Activate Kupffer Cells Isolated from Human Liver Tissues
HCV-Related Proteins Activate Kupffer Cells Isolated from Human Liver Tissues
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DOI：
10.1007/s10620-010-1395-y
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发表时间：
2011-04-01
影响因子：
3.1
通讯作者：
Fujii, Hideki
中科院分区：
文献类型：
--
作者：
Hosomura, Naohiro;Kono, Hiroshi;Fujii, Hideki
据该实验室报道，HCV感染患者的库普弗细胞（KCs）活化。由于树突状细胞、单核细胞和巨噬细胞可被HCV相关蛋白刺激激活，因此本研究的具体目的是研究HCV相关蛋白在KCs激活中的作用，toll样受体（TLR） 4介导的KCs激活的信号通路，以及HCV感染对KCs功能的影响。从非癌性手术标本中分离的Kupffer细胞与hcv相关蛋白（Core、NS3、NS4和NS5）共培养，并评估细胞因子（tnf - α、IL-1 β和IL-10）和过氧化氢的产生。此外，研究了TLR2、TLR3或TLR4中和抗体和细胞松弛素B对KCs产生tnf - α的影响。Kupffer细胞在所有hcv相关蛋白的刺激下显著产生促炎细胞因子tnf - α，与LPS刺激的KCs产生的数值相同。重要的是，在NS3的情况下，这种产生被针对TLR4的中和抗体显著地减弱了约60%，而不是细胞松弛素b。在HCV感染的肝脏中，通过LPS刺激分离的KCs产生的tnf - α明显大于HCV/ hbv阴性的肝脏。这些结果表明，hcv相关蛋白可能导致hcv感染肝脏中KCs的长时间激活，导致炎症细胞因子的积累，从而导致DNA损伤和致癌。此外，感染和未感染HCV的患者的KCs功能存在差异。
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.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-alpha, IL-1 beta, 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-alpha by KCs were investigated.Kupffer cells produced markedly a proinflammatory cytokine TNF-alpha 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-alpha by isolated KCs stimulated with LPS was significantly greater in the HCV-infected livers than the HCV/HBV-negative livers.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.