A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes
A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes
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DOI：
10.1046/j.1365-2567.1996.d01-777.x
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发表时间：
1996-12-01
期刊：
影响因子：
6.4
通讯作者：
Shinomiya, T
中科院分区：
文献类型：
--
作者：
Suzuki, S;Li, XK;Shinomiya, T
FTY 720是一种独特的免疫抑制药物，通过修饰来自Isaria sinclaiirii的代谢产物而产生。用FTY 720体外处理人单核细胞导致细胞活力的剂量依赖性降低。这些处理过的细胞在琼脂糖凝胶电泳上表现出特征性的DNA梯状条带形成。转染人bcl-2基因的Jurkat细胞对FTY 720耐药，其neo型对FTY 720敏感。早在与FTY 720孵育后2小时，就观察到人单核细胞中细胞死亡的快速加速。细胞内Bax蛋白在培养后1小时显著增加，存活细胞中Bax蛋白在培养后2小时和3小时显著降低。与Bax蛋白降低同时，Bcl-2蛋白在培养后2小时开始逐渐降低。因此，在FTY 720处理后，Bcl-2与Bax的比率立即由于Bax的表达增强而降低，导致细胞快速死亡加速。在培养后2和3小时的存活细胞（FTY 720抗性细胞）显示出与对照细胞中观察到的类似的Bcl-2与Bax的比率。这些结果表明，FTY 720显示bcl-2相关的人单核细胞凋亡的细胞死亡。
FTY720 is a unique immunosuppressive drug produced by modification of a metabolite from Isaria sinclairii. In vitro treatment of human mononuclear cells with FTY720 resulted in a dose-dependent reduction of cell viability. These treated cells demonstrated characteristic DNA ladder formation on agarose gel electrophoresis. Jurkat cells transfected with human bcl-2 gene were resistant to FTY720; their neo type was susceptible to the drug. A rapid acceleration of cell death in human mononuclear cells was seen as early as 2 hr after incubation with FTY720. The intracellular Bax protein increased remarkably 1 hr after the culture; it markedly decreased in the surviving cells at 2 and 3 hr. Coincidental to the Bax decrease, Bcl-2 progressively decreased beginning 2 hr after the culture. Thus, the ratio of Bcl-2 to Bax was decreased by the enhanced expression of Bax immediately after FTY720-treatment, resulting in rapid cell death acceleration. The surviving cells (FTY720-resistant cells) at 2 and 3 hr after culture showed a similar ratio of Bcl-2 to Bax as was observed in the control cells. These results suggest that FTY720 displays bcl-2-associated apoptotic cell death in human mononuclear cells.