Morice W G, Brunn G J, Wiederrecht G, Siekierka J J, Abraham R T
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905.
J Biol Chem. 1993 Feb 15;268(5):3734-8.
The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL-2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1-phase, just prior to entry of the cells into S-phase. In contrast, RAP-treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34cdc2 kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2-dependent increase in p34cdc2 kinase activity was blocked by RAP. The RAP sensitivity of the p34cdc2 activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.
大环内酯类药物雷帕霉素（RAP）是白细胞介素-2（IL-2）诱导的T细胞增殖的有效抑制剂。目前的模型表明，RAP与其细胞内受体FK506结合蛋白结合时，会干扰细胞从G1期进入S期进行细胞周期进程所需的IL-2受体偶联信号通路。在此我们表明，RAP处理在G1期晚期、细胞进入S期之前抑制了IL-2依赖性细胞毒性T细胞系CTLL-2的生长。相比之下，经RAP处理的CTLL-2细胞保留了以增强的溶细胞活性对IL-2作出反应的能力，这表明RAP并非细胞对IL-2反应性的一般抑制剂。随后的研究表明，IL-2刺激引发了p34cdc2激酶的延迟激活，其时间与G1期到S期的转变相关。IL-2依赖性的p34cdc2激酶活性增加被RAP阻断。p34cdc2激活机制对RAP的敏感性表明该信号通路参与了IL-2刺激的T细胞中S期进程的控制。
