Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway.
The signaling pathways that couple tumor necrosis factor-alpha (TNFalpha) receptors to functional, especially inflammatory, responses have remained elusive. We report here that TNFalpha 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 TNFalpha 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 TNFalpha on endothelial cells leading to extracellular signal-regulated kinases and NF-kappaB activation, whereas ceramide or sphingosine was not. Furthermore, N, N-dimethylsphingosine, an inhibitor of SKase, profoundly inhibited TNFalpha-induced extracellular signal-regulated kinases and NF-kappaB activation and adhesion protein expression. Thus we demonstrate that the SKase pathway through the generation of S1P is critically involved in mediating TNFalpha-induced endothelial cell activation.
Xia
P
P
Division of Human Immunology, The Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science and University of Adelaide, Adelaide, SA 5000, Australia.
Gamble
J R
JR
Rye
K A
KA
Wang
L
L
Hii
C S
CS
Cockerill
P
P
Khew-Goodall
Y
Y
Bert
A G
AG
Barter
P J
PJ
Vadas
M A
MA
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008246:Lysophospholipids; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D015398:Signal Transduction; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*; D000099157:Sphingosine Kinase
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019040:E-Selectin; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D013109:Sphingomyelins; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000099157:Sphingosine Kinase; C064769:N-acetylsphingosine; C060506:sphingosine 1-phosphate; C061800:N,N-dimethylsphingosine