Tumor necrosis factor-α induces adhesion molecule expression through the sphingosine kinase pathway
Tumor necrosis factor-α induces adhesion molecule expression through the sphingosine kinase pathway
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DOI：
10.1073/pnas.95.24.14196
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发表时间：
1998-11-24
影响因子：
11.1
通讯作者：
Vadas, MA
中科院分区：
文献类型：
--
作者：
Xia, P;Gamble, JR;Vadas, MA
将肿瘤坏死因子-α（TNF α）受体与功能性反应（尤其是炎症反应）偶联的信号通路仍然难以捉摸。我们在这里报告，TNF α诱导内皮细胞活化，测量的粘附蛋白E-选择素和血管粘附分子-1的表达，通过鞘氨醇激酶（SKase）信号通路。用TNF α处理人脐静脉内皮细胞导致快速SKase活化和鞘氨醇l-磷酸（S1 P）生成。SLP，而不是神经酰胺或鞘氨醇，是一个强大的剂量依赖性刺激剂的粘附蛋白表达。S1 P能够模拟TNF α对内皮细胞的作用，导致细胞外信号调节激酶和NF-κ B活化，而神经酰胺或鞘氨醇则不能。此外，N，N-二甲基鞘氨醇，SKase的抑制剂，深刻抑制TNF α诱导的细胞外信号调节激酶和NF-κ B活化和粘附蛋白表达。因此，我们证明SKase途径通过产生SLP是关键参与介导TNF α诱导的内皮细胞活化。
The signaling pathways that couple tumor necrosis factor-alpha (TNF alpha) receptors to functional, especially inflammatory, responses have remained elusive. We report here that TNF alpha induces endothelial cell activation, as measured by the expression of adhesion protein E-selectin and vascular adhesion molecule-1, through the sphingosine kinase (SKase) signaling pathway. Treatment of human umbilical vein endothelial cells with TNF alpha resulted in a rapid SKase activation and sphingosine l-phosphate (S1P) generation. SLP, but not ceramide or sphingosine, was a potent dose-dependent stimulator of adhesion protein expression. S1P was able to mimic the effect of TNF alpha on endothelial cells leading to extracellular signal-regulated kinases and NF-KB activation, whereas ceramide or sphingosine was not. Furthermore, N,N-dimethylsphingosine, an inhibitor of SKase, profoundly inhibited TNF alpha-induced extracellular signal-regulated kinases and NF-KB activation and adhesion protein expression. Thus we demonstrate that the SKase pathway through the generation of SLP is critically involved in mediating TNF alpha-induced endothelial cell activation.