Activation of Sphingosine Kinase by Tumor Necrosis Factor-α Inhibits Apoptosis in Human Endothelial Cells*
Activation of Sphingosine Kinase by Tumor Necrosis Factor-α Inhibits Apoptosis in Human Endothelial Cells*
复制标题
DOI：
10.1074/jbc.274.48.34499
复制
发表时间：
1999-11
期刊：
影响因子：
--
通讯作者：
P. Xia;Lijun Wang;J. Gamble;M. Vadas
中科院分区：
文献类型：
--
作者：
P. Xia;Lijun Wang;J. Gamble;M. Vadas
人脐静脉内皮细胞（HUVEC）与大多数正常细胞一样，对肿瘤坏死因子-α（TNF）诱导的细胞凋亡具有抵抗性，尽管TNF可激活鞘磷脂酶并产生神经酰胺（一种已知的细胞凋亡诱导剂）。在这里，我们报告说，TNF激活另一个关键酶，鞘氨醇激酶（SphK），在鞘磷脂代谢途径，导致生产鞘氨醇-1-磷酸（S1 P）和S1 P是一个有效的拮抗剂TNF介导的细胞凋亡。TNF诱导的SphK激活是独立的鞘磷脂酶和神经酰胺酶的活动，表明TNF直接影响这种酶，而不是通过对鞘磷脂降解的质量效应。与正常HUVEC相反，在自发转化的内皮细胞系（C11）中，TNF刺激未能激活SphK并诱导细胞凋亡，其特征在于形态学和生化标准。加入外源性S1 P或用佛波酯增加内源性S1 P均能明显保护C11细胞株免受TNF诱导的凋亡。相反，N，N-二甲基鞘氨醇，SphK的抑制剂，深刻敏化正常HUVEC杀死TNF。因此，我们表明，激活SphK的TNF是一个重要的信号保护从TNF的内皮细胞凋亡效应。
Human umbilical vein endothelial cells (HUVEC), like most normal cells, are resistant to tumor necrosis factor-α (TNF)-induced apoptosis in spite of TNF activating sphingomyelinase and generating ceramide, a known inducer of apoptosis. Here we report that TNF activates another key enzyme, sphingosine kinase (SphK), in the sphingomyelin metabolic pathway resulting in production of sphingosine-1-phosphate (S1P) and that S1P is a potent antagonist of TNF-mediated apoptosis. The TNF-induced SphK activation is independent of sphingomyelinase and ceramidase activities, suggesting that TNF affects this enzyme directly other than through a mass effect on sphingomyelin degradation. In contrast to normal HUVEC, in a spontaneously transformed endothelial cell line (C11) TNF stimulation failed to activate SphK and induced apoptosis as characterized by morphological and biochemical criteria. Addition of exogenous S1P or increasing endogenous S1P by phorbol ester markedly protected C11 cell line from TNF-induced apoptosis. Conversely,N,N-dimethylsphingosine, an inhibitor of SphK, profoundly sensitized normal HUVEC to killing by TNF. Thus, we demonstrate that the activation of SphK by TNF is an important signaling for protection from the apoptotic effect of TNF in endothelial cells.