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

^*Division of Human Immunology, ^†Department of Lipid Research, The Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science and University of Adelaide, and ^§Department of Immunology, Women’s and Children’s Hospital, Adelaide, SA 5000, Australia

Abstract

The signaling pathways that couple tumor necrosis factor-α (TNFα) receptors to functional, especially inflammatory, responses have remained elusive. We report here that TNFα 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 TNFα 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 TNFα on endothelial cells leading to extracellular signal-regulated kinases and NF-κB activation, whereas ceramide or sphingosine was not. Furthermore, N,N-dimethylsphingosine, an inhibitor of SKase, profoundly inhibited TNFα-induced extracellular signal-regulated kinases and NF-κB activation and adhesion protein expression. Thus we demonstrate that the SKase pathway through the generation of S1P is critically involved in mediating TNFα-induced endothelial cell activation.

Footnotes

↵ ¶ To whom reprint requests should be addressed. e-mail: Mathew.Vadas{at}imvs.sa.gov.au.
Comunicated by Jacques F. A. P. Miller, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Abbreviations: DMS, N,N-dimethylsphingosine; ERK, extracellular signal-regulated kinase; HUVEC, human umbilical vein endothelial cells; SKase, sphingosine kinase; S1P, sphingosine 1-phosphate; TNFα, tumor necrosis factor-α; VCAM-1, vascular adhesion molecule-1; JNK, c-JUN N-terminal kinase.
† J.R.G. and M.A.V. contributed equally to this work.