Activation of sphingosine kinase by tumor necrosis factor-α inhibits apoptosis in human endothelial cells
Date
1999
Authors
Xia, Pu
Wang, Lijun
Gamble, Jennifer R.
Vadas, Mathew Alexander
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Biological Chemistry, 1999; 274(48):34499-34505
Statement of Responsibility
Pu Xia, Lijun Wang, Jennifer R. Gamble and Mathew A. Vadas
Conference Name
Abstract
Human umbilical vein endothelial cells (HUVEC), like most normal cells, are resistant to tumor necrosis factor-α (TNF)-induced apoptosis in spite of TNF activating sphingomyelinase and generating ceramide, a known inducer of apoptosis. Here we report that TNF activates another key enzyme, sphingosine kinase (SphK), in the sphingomyelin metabolic pathway resulting in production of sphingosine-1-phosphate (S1P) and that S1P is a potent antagonist of TNF-mediated apoptosis. The TNF-induced SphK activation is independent of sphingomyelinase and ceramidase activities, suggesting that TNF affects this enzyme directly other than through a mass effect on sphingomyelin degradation. In contrast to normal HUVEC, in a spontaneously transformed endothelial cell line (C11) TNF stimulation failed to activate SphK and induced apoptosis as characterized by morphological and biochemical criteria. Addition of exogenous S1P or increasing endogenous S1P by phorbol ester markedly protected C11 cell line from TNF-induced apoptosis. Conversely,N,N-dimethylsphingosine, an inhibitor of SphK, profoundly sensitized normal HUVEC to killing by TNF. Thus, we demonstrate that the activation of SphK by TNF is an important signaling for protection from the apoptotic effect of TNF in endothelial cells.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 1999 by The American Society for Biochemistry and Molecular Biology, Inc.