弹性蛋白肽对树突状细胞诱导T细胞向Th17分化的机制

The inflammation of COPD caused by Cigarette smoke lead to degradation of lung tissue, which generate elastin pepitedes(EP).EP can promote dendritic cells(DCs) to induce differentiation of Th17 from T cells, which participate the inflammatory process of COPD. The CD40-CD40L pathway of DCs contacted with T cells and the forkhead box o 3(FOXO3) are the important factors which impact DCs polarize T cells to Th17.Whereas whether the EP stimulate DCs polarizing T cells to Th17 by the mechanism of CD40-CD40L pathway and FOXO3 is unclear. We previously demonstrated that Th17 expression had increased in the lung parenchyma of patient with COPD and of rat with emphysema, which associated with inflammation of COPD. So based these researches, we further investigate the effect of EP on pathway of CD40-CD40L and FOXO3 which DC polarize T cells to Th17:Firstly we observe the effect of EP on the co-stimulatory molecules and FOXO3 of DCs. Secondly we investigate the he effect of EP on DCs polarizing T cells to Th17 under the condition of blocking and non-blocking the CD40-CD40L pathway. This research will further recognize the mechanism of immune inflammation in COPD,and provide the new target for treatment of COPD.

吸烟引起COPD的炎症导致肺组织降解产生弹性蛋白肽（EP），EP可促进树突状细胞（DCs）诱导T细胞分化为Th17参与COPD炎症发病过程，DCs与T细胞的CD40-CD40L通路和DCs中的 FOXO3是影响DCs诱导T细胞分化为Th17的重要因素，然而EP刺激DCs诱导T细胞向Th17分化是否通过CD40-CD40L通路及FOXO3机制尚无研究。我们前期研究发现Th17细胞在COPD患者及烟草烟雾暴露大鼠肺实质中增多并与炎症相关，故本项目在前期研究的基础上进一步探讨EP刺激下DC对T细胞分化为Th17的CD40-CD40L通路及FOXO3影响。首先探EP刺激下DCs的共刺激分子和FOXO3表达，进而观察在阻断和不阻断CD40-CD40L下EP刺激DC细胞对T细胞分化成Th17的影响。以上研究为本课题的特色与创新点，研究开展将有助于深化认识COPD中免疫炎症的机制以及寻找新的治疗靶点。

吸烟引起COPD的炎症导致肺组织降解产生弹性蛋白肽（EP），EP可促进树突细胞（DCs）诱导T细胞分化为Th17参与COPD炎症发病过程，DCs与T细胞的CD40-CD40L通路是影响DCs诱导T细胞分化为Th17的重要因素。本课题围绕弹性蛋白肽－树突状细胞活化（共刺激分子如 CD40,CD80表达上调）－CD4+T淋巴细胞分化展开三者关系变化的研究，探讨了弹性蛋白肽刺激树突状细胞对T淋巴细胞向 TH17分化的影响。研究结果：1.体外实验：EP可促进小鼠骨髓来源的mDC成熟（CD40,CD80,MHCII表达上调），细胞上清炎症因子IL-6及TGF-β升高。2.体内实验：a. 弹性蛋白肽所致小鼠肺气肿与烟熏所致差异无统计学意义；b.EP可促进外周血、脾和肺内CD4+T细胞向Th17分化与烟熏组趋势一致；c. RORγt mRNA、IFN-γmRNA的相对表达量均升高，肺泡灌洗液中IL-6及TGF-β升高；d.阻断CD40/CD40L通路可以抑制EP暴露下树突状细胞诱导Th17分化。本实验阐明了EP在COPD获得性免疫反应启动的作用。此外，说明了CD40/CD40L信号通路在EP暴露下树突状细胞诱导TH17分化的重要作用，为COPD的防治提供可能的有效的靶点和药物。