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苯并噻唑衍生物BD759抗T细胞增殖的机制研究
罗兴燕, 邹强, 孙海,胡松,唐信威,何莉,夏超亚,王茂田,刘阳,赖翼
中国药学杂志 ›› 2015, Vol. 50 ›› Issue (15) : 1313-1318.
PDF(1428 KB)
PDF(1428 KB)
苯并噻唑衍生物BD759抗T细胞增殖的机制研究
Suppressive Effect of a Novel Benzothiazole Derivative BD759 on T Cell Proliferation
目的 探讨新型苯并噻唑衍生物BD759抑制T细胞增殖的作用机制。 方法 流式细胞术检测T细胞增殖、CD25表达及细胞周期。酶联免疫吸附法测定BD759对活化T细胞分泌白细胞介素-2、白细胞介素-4、白细胞介素-6、白细胞介素-10、白细胞介素-17A及干扰素-γ等细胞因子的影响。 结果 BD759抑制抗人CD3和CD28mAbs刺激的T 细胞增和混合淋巴细胞反应,IC50分别为(3.5 ± 0.7) 和(3.3 ± 0.9) μmol·L-1。BD759对人静息T细胞和外周血单个核细胞无细胞毒性。BD759不抑制活化的T细胞表达CD25和分泌细胞因子白细胞介素-2 、白细胞介素-4及白细胞介素-10,但显著抑制白细胞介素-6、白细胞介素-17A和干扰素-γ的产生,并且阻滞细胞周期于G0/G1期。 结论 新型苯并噻唑衍生物BD759不影响T细胞的活化,但通过阻滞细胞周期于G0/G1期抑制活化的T细胞增殖,并抑制白细胞介素-6、白细胞介素-17A和干扰素-γ等促炎细胞因子的分泌。BD759有望作为先导化合物,开发用于自身免疫性疾病与器官移植的新型药物。
OBJECTIVE To determine the immunosuppressive activity of a novel benzothiazole derivative BD759 on T cell proliferation and its potential mode of action. METHODS T cell proliferation, CD25 expression and cell cycle distribution were measured by flow cytometer. Cytokine levels, including IL-2, IL-4, IL-6, IL-10, IL-17A and IFN-γ, were determined by ELISA. RESULTS BD759 significantly inhibited human T cell proliferation, stimulated either by anti-CD3/anti-CD28 monoclonal antibodies or by an alloantigen, in a dose-dependent manner with IC50 values of (3.5±0.7) and (3.3±0.9) μmol·L-1, respectively. No obvious cytotoxic effects of BD759 were observed on human resting nave T cells and peripheral blood mononuclear cells in our experimental conditions. Furthermore, BD759 did not inhibit CD25 expression or IL-2, IL-4 and IL-10 secretion, but inhibited IL-6, IL-17A and IFN-γ production and induced cell cycle arrest at the G0/G1 phase in activated T cells. CONCLUSION These data indicate that BD759 has no effect on T cell activation, but induces T cell cycling arrest at G0/G1 phase. BD759 also inhibits the secretion of inflammatory cytokines, such as IL-6, IL-17A and IFN-gamma. Thus, BD759 has the potential to be used as a lead compound for the design and development of new immunosuppressants for treating autoimmune diseases and preventing graft rejection.
苯并噻唑衍生物 / T细胞增殖 / 免疫抑制剂 / 细胞周期 {{custom_keyword}} /
benzothiazol derivate / T cell proliferation / immunosuppressants / cell cycle {{custom_keyword}} /
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国家自然科学基金资助项目(81273530,81302786);四川省高校科研创新团队(13TD0028);四川省教育厅科研项目(15ZB0233,15ZB0235)
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