人参皂苷CK选择性激动糖皮质激素受体抑制胶原性关节炎T细胞功能及其机制

项目名称： 人参皂苷CK选择性激动糖皮质激素受体抑制胶原性关节炎T细胞功能及其机制

项目编号： No.81503084

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈镜宇

作者单位： 安徽医科大学

项目金额： 17.9万元

中文摘要： 人参皂苷CK（CK）是具有我国自主知识产权的新型单体，课题组研究表明CK有明显抗炎和免疫调节活性，抑制T细胞过度活化是其主要特点，但机制不清。糖皮质激素受体（GR）活化后通过抑制NF-κB发挥抗炎作用，同时诱导GR反应元件（GRE）转录激活而产生不良反应。课题组发现CK对T细胞活化的抑制作用可被GR拮抗剂阻断，且CK不影响实验动物的血糖和体重，提示CK对T细胞活化的抑制作用可能与其激活GR有关，且可能不诱导GRE的转录激活。那么CK可否作为GR的选择性调节剂，通过下调NF-κB抑制T细胞活化，而不诱导GRE的转录激活，较少引起糖皮质激素（GC）样不良反应？未见报道。本项目拟建立胶原性关节炎模型，体外实验探讨GR在CK抑制T细胞功能中的作用及机制，体内实验研究CK是否有GC样不良反应以及与GR信号的关系，为揭示CK的抗炎免疫调节分子机制提供依据，为把CK开发为自主知识产权的原创药物提供基础。

中文关键词： 人参皂苷CK；糖皮质激素受体；T细胞；胶原性关节炎

英文摘要： Ginsenoside metabolite compound K (CK, 20-O-D-glucopyranosyl-20(S)-protopanaxadiol, C36H62O8) belongs to dammarane-type triterpene saponins according to its structure. It is a degradation product of ginsenoside in the intestine by bacteria and is the major form of ginsenoside absorbed into the body and can be transformed from ginsenoside by food microorganisms in vitro. The anti-inflammatory activity of CK has been identified in several studies. Our study demonstrated that CK exerted anti-inflammatory effect on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AA) animal models, and this effect was due to inhibiting the abnormal activation and differentiation of T cells. However, the mechanism of CK on suppressing T cell activation remains unclear..Classic glucocorticoid receptor (GR) targets gene promoter activation via interaction of homodimeric GR with glucocorticoid response elements (GRE) resulting in physiological effects and adverse effects. Glucocorticoids (GCs) also can block inflammation via interference of the liganded GR with the activity of pro-inflammatory transcription factors NF-κB, a mechanism known as transrepression Our study demonstrated that the effect of CK on inhibiting the abnormal T cell activation can be blocked by GR antagonist, and CK did not affect body weight and blood glucose level in vivo. All these results suggest that the effect of CK on suppressing T cell activation may be related to GR activation, and this activation of GR may not induce GRE transcriptional activation. This study was designed to identify whether CK exerted inhibitory effect on abnormal T cell function via inhibiting NF-κB, and at the same time did not induce GRE transcription activation resulting less adverse effects. To that end, T cells were isolated from collagen induced arthritis rats, the effect of CK on CIA T cell function was assayed, and role of GR was investigated in vitro. Then the potential adverse reaction of CK was investigated in vivo, at the same time, the effect of CK on GR signals was assayed. This study provides an interesting novel insight into the potential mechanism by which CK contributes to the anti-inflammatory effect in autoimmune conditions.

英文关键词： Ginsenoside compound K ;glucocorticoid receptor ;T cells ;collagen-induced arthritis