海洋真菌吲哚生物碱通过STAT3通路调控Th17/Treg平衡的分子机制

Autoimmune diseases are chronic disorders that affect up to hundreds of million people. The Th17/Treg imbalance may be responsible for the development and progression of autoimmune and inflammatory diseases. The combination of the treatment that manipulates key cytokines with the treatment that target Th17/Treg imbalance may lead to novel and effective immunotherapies for autoimmune and inflammatory diseases. In our investigation, the fermentation broth of the marine-derived fungus Aspergillus fumigatus YK-7 exhibited potent immunosuppressive effect. Indole alkaloids were isolated from this fermentation broth and evaluated for immunosuppressive effects in vitro. A new indole alkaloid exhibited most potent activity. The present study was carried out for immunosuppressive effect and regulatory mechanism of the new indole alkaloid on Th17 and Treg cell balance, according to the effects of Th17 and Treg cell differentiation, related transcription and inflammatory factors gene and protein expression, and STAT3 signaling pathway. Our study will provide theoretical and experimental basis to development of new immunosuppressive drugs with clear target and mechanism for the treatment of autoimmune diseases.

Th17/Treg细胞失衡与多种自身免疫性疾病及炎症性疾病的发生、发展密切相关。调控体内Th17/Treg平衡而抑制异常免疫反应成为自身免疫性疾病及炎症性疾病防治药物研究的重要方向。前期采用生物活性追踪与代谢产物分离相结合的方法对具有免疫抑制活性海洋真菌Aspergillus fumigatus YK-7进行系统的次级代谢产物研究，获得系列吲哚生物碱类化合物，具有良好的免疫抑制作用。本项目拟对其中一个新型吲哚生物碱免疫抑制作用及机制进行深入研究，通过检测吲哚生物碱体内外对Th17、Treg细胞分化及相关转录因子与炎症因子RORγt、IL-17A、IL-17F、Foxp3等基因和蛋白表达水平影响，阐明其对Th17/Treg细胞平衡的免疫调控作用，探讨其影响STAT3信号转导通路的免疫学分子机制，为开发靶点与机制明确的新型免疫抑制类药物提供新的理论基础与实验依据。

Th17/Treg细胞失衡与多种自身免疫性疾病及炎症性疾病的发生、发展密切相关。调控体内Th17/Treg平衡而抑制异常免疫反应，成为自身免疫性疾病及炎症性疾病防治药物研究的重要方向。本项目以调控Th17/Treg细胞平衡而抑制异常免疫反应为切入点，对一新型海洋真菌来源吲哚生物碱免疫抑制作用及机制进行深入系统研究。体内外实验结果显示该吲哚生物碱通过STAT3转导通路抑制Th17细胞分化及相关促炎症细胞因子的表达，并增强Treg细胞的活性，进而调控Th17/Treg细胞平衡而发挥其免疫抑制作用。本项目为开发靶点与机制明确的新型免疫抑制类药物提供新的理论基础与实验依据。