棕榈酸酯诱导人间充质干细胞炎症因子表达的作用机制研究

Low-grade systemic inflammation status in type 2 diabetes has come into the spotlight because of its involvement in the pathogenesis of diabetes. Numerous studies have shown that free fatty acids (FFA) stimulate production of inflammatory cytokines in many cell types. Mesenchymal stem cells (MSCs), one type of the adult stem cells, possess immunoregulatory and regenerative properties. Our previous research showed that palmitate, the dominant saturated FFA, increased the expression of inflammatory cytokines in MSCs. In current study, we will focus on the mechanism of palmitate stimulation, Many questions, including the role of Toll-like receptors in palmitate exposure, whether palmitate signaling through Rac1 activation and ROS generation, which signaling pathway involves in palmitate-induced IL-6 and IL-8 production, will be investigated. Next, we will find chemical drugs that effectively inhibit the effects of plamitate. Production of abnormal inflammatory cytokines in bone marrow-derived MSCs (BM-MSCs) of diabetic patiens and its molecular mechanisms also will be confirmed. Our study aims to demonstrate that palmitate is one factor that impairs immunoregulatory properties of MSCs by inducing inflammatory cytokine expression. Our study provides new insight for etiology and treatment of diabetes.

探寻糖尿病发病机制是医学领域的研究热点。2型糖尿病的低炎状态备受瞩目，已有研究表明多种细胞受游离脂肪酸刺激表达炎症相关因子。间充质干细胞（MSCs）是参与体内免疫调节和组织修复的重要成体干细胞。我们的前期研究结果显示，饱和游离脂肪酸-棕榈酸酯（PA）促进MSCs中炎症因子表达。本项目将深入探讨PA促炎症因子表达的作用机制，阐明Toll样受体是参与PA诱导的膜受体，揭示Rac1活性升高及胞内ROS水平增加是促炎症因子表达的关键步骤，明确参与调控IL-6和IL-8基因表达升高的胞内信号通路；课题还将筛选对PA促炎反应有抑制作用的化学药物，阐明其作用机理；研究糖尿病患者骨髓来源MSCs是否存在炎症因子表达异常并分析其可能的分子机制。本课题从促进炎症因子表达的角度阐明PA是MSCs发挥免疫调节功能的不利因素，课题为糖尿病低炎状态的防治开辟了新的研究方向。

2型糖尿病的低炎状态备受瞩目，已有研究表明多种细胞受游离脂肪酸刺激表达炎症相关因子。间充质干细胞（MSCs）是参与体内免疫调节和组织修复的重要成体干细胞。我们的研究结果显示，饱和游离脂肪酸-棕榈酸酯（palmitate, PA）诱导MSCs凋亡，同时促进炎症相关因子IL-6、IL-8表达。本项目深入探讨PA促炎症因子表达的作用机制，阐明Toll样受体是参与PA诱导的膜受体，TLR2和TLR4基因敲减有抑制PA促炎的作用；揭示GTPase Rac1和CDC42活性升高及胞内ROS水平增加是促炎症因子表达的关键步骤，通过基因敲减明确CDC42是参与调控IL-6和IL-8基因表达升高的胞内信号分子。课题还筛选对PA促炎反应有抑制作用的化学药物，发现AMPK激动剂AICAR和2-DG是抑制PA脂毒性的有效分子。研究糖尿病患者骨髓来源MSCs，发现糖尿病患者MSC存在炎症因子表达异常升高，分析其中GTPase活性发现Rac1和CDC42活性升高。本课题从促进炎症因子表达的角度阐明PA是MSCs发挥免疫调节功能的不利因素，课题为糖尿病低炎状态的防治开辟了新的研究方向。