苯烯莫德通过mTOR信号通路调节Th17/Treg平衡治疗炎症性肠病的机制研究

Inflammatory bowel disease (IBD) is a kind of recurrent gastrointestinal inflammatory diseases with unknown etiology. Existing drugs are difficult to maintain its long-term relief, it is very important to develop new drugs with satisfactory therapeutic effect. Benvitimod is a non-hormonal small molecule drug that can inhibit the expression of a variety of proinflammatory cytokines. Our previous study found that benvitimod could improve the symptoms of DSS induced inflammatory bowel disease of the rat model and regulate the balance of Th17/Treg cells and the expression of sFGL2. Research shows that Th17/Treg imbalance is a key factor in the pathogenesis of inflammatory bowel disease. As a novel effector molecule of immunosuppressive effect of Treg cells, sFGL2 can promote the apoptosis of many kinds of cells, which is a hot research topic in recent years. Inhibition of mTOR signaling pathway can promote the activation of Treg cells. It is hypothesized that Benvitimod can activate Treg cells to secrete sFGL2 by inhibiting mTOR signaling pathway, promote the apoptosis of Th17 cells, regulate the balance of Th17/Treg and achieve the objective of treatment of inflammatory bowel disease. We will investigate the effects of benvitimod on mTOR signaling pathway, activation of Treg cell, production of sFGL2, apoptosis of Th17 cells and balance of Th17/Treg in vivo and in vitro. This study provides a theoretical support for the development of treatment of inflammatory bowel disease by benvitimod.

炎症性肠病（IBD）是一种病因未明、反复发作的胃肠道炎症性疾病。现有药物难以维持其长期缓解，研发疗效肯定的药物至关重要。苯烯莫德是一种非激素类小分子药物，能抑制多种炎症因子的表达。本课题组前期实验发现：苯烯莫德可改善DSS诱导的IBD大鼠模型的症状。文献表明：Th17/Treg失衡及mTOR信号通路激活是IBD发病的关键因素，而sFGL2是Treg细胞发挥免疫抑制作用的重要效应分子，可促进多种细胞的凋亡。我们推测苯烯莫德改善IBD的作用机制可能是：抑制mTOR信号通路进而激活Treg细胞分泌sFGL2，从而促进Th17细胞凋亡、调节Th17/Treg平衡。本项目将从体内、体外层面探讨苯烯莫德对mTOR信号通路、Treg细胞活化、sFGL2生成、Th17细胞凋亡，以及Th17/Treg平衡的影响。本研究为拓展苯烯莫德治疗IBD提供理论支持。

炎症性肠病(IBD)是一种病因未明、反复发作的胃肠道炎症性疾病。现有药物难以维持其长期缓解，研发疗效肯定的药物至关重要。苯烯莫德是一种非激素类小分子药物，能抑制多种炎症因子的表达。本研究对苯烯莫德灌肠液制作工艺进行改进，相比非极性溶剂溶解的苯烯莫德，提高了其治疗DSS诱导的IBD小鼠模型的疗效。药物局部作用能促进肠道屏障完整性，促进肠上皮细胞的增殖，无肝肾心功能毒性，减轻小鼠焦虑行为，并抑制肠炎相关性肠癌的发生。进一步，文献表明:Th17/Treg失衡是IBD发病的关键因素，而AhR是苯烯莫德的亲和力最强的蛋白受体，同时也是调节免疫的重要效应分子，对细胞增殖具有重要作用。本研究验证了苯烯莫德对Treg细胞无显著影响，促进炎性细胞凋亡，体外水平促进CD4+细胞凋亡，而蛋白水平低表达AhR抑制CD4+细胞系H9的凋亡，为拓展苯烯莫德治疗IBD提供理论支持。