高迁移率族蛋白1通过上调肝癌病人kupffer细胞Toll样受体和IL-33表达来促进Th17细胞的功能

项目名称： 高迁移率族蛋白1通过上调肝癌病人kupffer细胞Toll样受体和IL-33表达来促进Th17细胞的功能

项目编号： No.81201595

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： siamak sandoghchian shoto

作者单位： 南京医科大学

项目金额： 24万元

中文摘要： 炎症与肿瘤的发生发展密切相关，Kupffer细胞在调控Th17分化、促进肿瘤微环境形成中起重要作用，具体机制未明。HMGB1是目前已知的唯一与肿瘤形成有关的高迁移率族蛋白，能从坏死组织中释放出来，引起炎症反应。我们前期研究发现，肝癌组织中HMGB1 mRNA表达水平显著高于癌旁和正常组织，kupffer细胞中HMGB1受体TLR4表达增高，经体外HMGB1刺激后IL-33及IL-17分泌水平明显增加，提示Kupffer细胞上HMGB1表达增加可能是调控Th17分化、促进肿瘤形成的重要机制之一。本研究将从细胞和动物水平观察肝癌微环境对Kupffer细胞上HMGB1表达的影响，以及HMGB1表达增加与Th17分化之间的关系，并进一步阐明KCs细胞中TLR4介导的HMGB1参与炎症的机制及免疫信号通路，为肝癌的发病机理和防治策略提供理论依据。

中文关键词： 肝纤维化；白介素33；ST2；星状细胞；MAPK

英文摘要： There was a well known existed relationship of inflammation and carcinogenesis, but the exact role of Kupffer cells in Th17 differentiation and tumor micro-environment promotion are uncertain. HMGB1 released from necrotic tissues are the only identified High-mobility group protein which related to tumor-genesis and may induce inflammation. Here we find a significant up-regulation of HMGB1 mRNA in hepatic celluar carcinoma (HCC), and also a over-expression of TLR4 in Kupffer cells which is the receptor of HMGB1. At the other hand, after HMGB1 restimulation, IL-33 and IL-17A are increased in cultured Kupffer cells, indicating a potential link between HMGB1 up-regulation and Th17 differentiation or tumor micro-environment promotion. Therefore, we plan to examine the mechanism of HMGB1 expression on Kupffer cells under tumor micro-environment through in vitro and in vivo methods. At the same time, the internal relationship of HMGB1 and Th17 differentiation as well as the signal pathway in TLR4 inducing HMGB1 expression will also be investigated. Those findings may potent provide a new strategy against HCC genesis and may benefit patients from sustained inflammation.

英文关键词： liver fibrosis；IL-33；ST2；HSCs；MAPK