Suzuki S, Li X K, Enosawa S, Shinomiya T
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Centre, Tokyo, Japan.
Immunology. 1996 Dec;89(4):518-23. doi: 10.1046/j.1365-2567.1996.d01-777.x.
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.
FTY720是一种通过对蝉拟青霉的代谢产物进行修饰而产生的独特免疫抑制药物。用FTY720对人单核细胞进行体外处理导致细胞活力呈剂量依赖性降低。这些处理过的细胞在琼脂糖凝胶电泳上显示出特征性的DNA梯带形成。转染了人bcl-2基因的Jurkat细胞对FTY720有抗性；其neo型对该药物敏感。早在用FTY720孵育2小时后，就观察到了人单核细胞中细胞死亡的快速加速。培养1小时后，细胞内Bax蛋白显著增加；在2小时和3小时时，存活细胞中的Bax蛋白明显减少。与Bax减少同时发生的是，培养2小时后Bcl-2逐渐减少。因此，在FTY720处理后，Bax的表达增强导致Bcl-2与Bax的比率降低，从而加速细胞死亡。培养2小时和3小时后的存活细胞（FTY720抗性细胞）显示出与对照细胞中观察到的相似的Bcl-2与Bax比率。这些结果表明，FTY720在人单核细胞中表现出与bcl-2相关的凋亡性细胞死亡。
