Study for the signal transduction of cell growth using a new immunosuppressant ISP-1

ISP-1是一种新型的免疫抑制剂，其结构与鞘氨醇同源。发现ISP-1通过抑制丝氨酸棕榈酰转移酶抑制IL-2依赖性细胞毒性T细胞系CTLL-2的增殖，所述丝氨酸棕榈酰转移酶催化鞘脂生物合成的第一步。流式细胞术分析ISP-1的作用表明，ISP-1诱导的细胞数量减少不是由于抑制CTLL-2细胞的细胞周期进程，而是由于诱导细胞凋亡。ISP-1诱导的细胞凋亡被鞘氨醇的加入抑制，这表明这种细胞凋亡是由丝氨酸棕榈酰转移酶的抑制引起的鞘脂的细胞内水平的降低而引发的。另一种IL-2依赖性细胞系F7，其来源于小鼠pro-B细胞系，未显示ISP-1依赖性凋亡，表明ISP-1的作用可能对某种类型的T细胞谱系如CTLL-2具有特异性。另一方面，高剂量鞘氨醇本身可诱导CTLL-2细胞凋亡。在F7细胞中也观察到这种鞘氨醇依赖性细胞凋亡。总之，维持鞘氨醇和/或其生物合成衍生物的细胞内浓度对于防止细胞凋亡是非常重要的，并且在CTLL-2细胞中低和高细胞内水平均诱导细胞凋亡。

ISP-1 is a new type of potent immunosuppessant, the structure of which is homologous to sphingosine. ISP-1 was found to suppress the proliferation of an IL-2-dependent cytotoxic T cell line, CTLL-2, through the inhibition of serine palmitoyltransferase, which catalyzes the first step of sphingolipid biosynthesis. Flow cytometric analysis of the effect of ISP-1 revealed that the decrease in cell number induced by ISP-1 was not due to inhibition of the cell cycle progression of CTLL-2 cells but to the induction of apoptosis of the cells. The apoptosis induced by ISP-1 was inhibited by the addition of sphingosine, suggesting that this apoptosis is triggered by the decrease in the intracellular levels of sphingolipids caused by the inhibition of serine palmitoyltransferase. Another IL-2-dependent cell line, F7, which was derived from a mouse pro-B cell line, did not show ISP-1 dependent apoptosis, suggesting that the effect of ISP-1 may be specific for a certain type of T cell lineage such as CTLL-2. On the oter hand, a high dose of sphingosine by itself induced the apoptosis of CTLL-2 cells. This sphingosine-dependent apoptosis was also observed with F7 cells. Taken together, the maintenance of intracellular concentration of sphingosine and/or its biosynthetic derivative (s) is very important to prevent from apoptosis, and both the hypo-and hyper-intracellular levels induced apoptosis in CTLL-2 cells.