期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：24
页码：14196-14201
DOI：10.1073/pnas.95.24.14196
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The signaling pathways that couple tumor necrosis factor- (TNF) receptors to functional, especially inflammatory, responses have remained elusive. We report here that TNF 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 resulted in a rapid SKase activation and sphingosine 1-phosphate (S1P) generation. S1P, but not ceramide or sphingosine, was a potent dose-dependent stimulator of adhesion protein expression. S1P was able to mimic the effect of TNF on endothelial cells leading to extracellular signal-regulated kinases and NF-{kappa}B activation, whereas ceramide or sphingosine was not. Furthermore, N,N-dimethylsphingosine, an inhibitor of SKase, profoundly inhibited TNF-induced extracellular signal-regulated kinases and NF-{kappa}B activation and adhesion protein expression. Thus we demonstrate that the SKase pathway through the generation of S1P is critically involved in mediating TNF-induced endothelial cell activation.
