Kirenol attenuates experimental autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17 cells and inducing apoptosis of effector T cells.
Kirenol attenuates experimental autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17 cells and inducing apoptosis of effector T cells.
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基里诺通过抑制Th1和Th17细胞的分化并诱导效应T细胞的凋亡来减轻实验性自身免疫性脑脊髓炎。
DOI：
10.1038/srep09022
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发表时间：
2015-03-12
影响因子：
4.6
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Xiao J;Yang R;Yang L;Fan X;Liu W;Deng W
实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症（MS）的一种模型，其特征是由自身反应性T细胞介导的中枢神经系统脱髓鞘。Kirenol是一种从草中分离得到的生物活性物质，具有很强的抗炎活性。本文研究了氯丙二醇对EAE的影响。Kirenol治疗可显著延缓EAE小鼠的发病并降低临床评分。Kirenol处理降低血清中IFN-γ和IL-17A的表达以及引流淋巴结中Th1和Th17细胞的比例。kirenol处理的EAE小鼠淋巴细胞激活减少，mog激活的CD4+ T细胞凋亡增加。对健康动物进行氯硝唑处理后，未免疫小鼠的淋巴细胞未受影响。进一步的体外研究表明，kirenol抑制mog特异性淋巴细胞的活力，诱导mog特异性CD4+ T细胞凋亡，并呈剂量和时间依赖性。Kirenol处理可上调Bax，下调Bcl-2，增加caspase-3的激活和细胞色素c的释放，表明Kirenol诱导的细胞凋亡可能通过线粒体途径参与。此外，在淋巴细胞中使用泛caspase抑制剂z-VAD-fmk或更特异性的caspase 3抑制剂Ac-DEVD-CHO预处理可减少kirenol诱导的细胞凋亡。我们的研究结果表明，基诺尔是治疗多发性硬化症的有效药物。
Experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is characterized by CNS demyelination mediated by autoreactive T cells. Kirenol, a biologically active substance isolated from Herba Siegesbeckiae, has potent anti-inflammatory activities. Here we investigated effects of kirenol on EAE. Kirenol treatment markedly delayed onset of disease and reduced clinical scores in EAE mice. Kirenol treatment reduced expression of IFN-γ and IL-17A in the serum and proportion of Th1 and Th17 cells in draining lymph nodes. Priming of lymphocytes was reduced and apoptosis of MOG-activated CD4+ T cells was increased in kirenol treated EAE mice. Kirenol treatment of healthy animals did not affect the lymphocytes in these non-immunized mice. Further in vitro studies showed that kirenol inhibited viability of MOG-specific lymphocytes and induced apoptosis of MOG-specific CD4+ T cells in a dose- and time-dependent manner. Kirenol treatment upregulated Bax,downregulated Bcl-2,and increased activation of caspase-3 and release of cytochrome c, indicating that a mitochondrial pathway was involved in kirenol induced apoptosis. Moreover, pretreatment with either a pan-caspase inhibitor z-VAD-fmk or a more specific caspase 3 inhibitor Ac-DEVD-CHO in lymphocytes reduced kirenol induced apoptosis. Our findings implicate kirenol as a useful agent for the treatment of MS.
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