TUMOR-NECROSIS-FACTOR-ALPHA INDUCES ADHESION MOLECULE EXPRESSION THROUGH THE SPHINGOSINE KINASE PATHWAY

The signaling pathways that couple tumor necrosis factor-alpha (TNF al pha) receptors to functional, especially inflammatory, responses have remained elusive. We report here that TNF alpha induces endothelial ce ll activation, as measured by the expression of adhesion protein E-sel ectin and vascular adhesion molecule-1, through the sphingosine kinase (SKase) signaling pathway. Treatment of human umbilical vein endothel ial cells with TNF alpha resulted in a rapid SKase activation and sphi ngosine l-phosphate (S1P) generation. SLP, but not ceramide or sphingo sine, was a potent dose-dependent stimulator of adhesion protein expre ssion. S1P was able to mimic the effect of TNF alpha on endothelial ce lls leading to extracellular signal-regulated kinases and NF-KB activa tion, whereas ceramide or sphingosine was not. Furthermore, N,N-dimeth ylsphingosine, an inhibitor of SKase, profoundly inhibited TNF alpha-i nduced extracellular signal-regulated kinases and NF-KB activation and adhesion protein expression. Thus we demonstrate that the SKase pathw ay through the generation of SLP is critically involved in mediating T NF alpha-induced endothelial cell activation.