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© The Rockefeller University Press, 0022-1007/1999/7/1/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 1, July 1, 1999 1-8

Original Article

The Balance between Sphingosine and Sphingosine-1-Phosphate Is Decisive for Mast Cell Activation after Fcisin Receptor I Triggering

Eva E. Prieschla, Robert Csongaa, Veronica Novotnya, Gary E. Kikuchib, and Thomas Baumrukera

a From the Department of Immunology, Novartis Research Institute, A-1235 Vienna, Austria
b Genetic Therapy, Inc. (A Novartis Company), Gaithersburg, Maryland 20878

Over the last few years, sphingolipids have been identified as potent second messenger molecules modulating cell growth and activation. A newly emerging facet to this class of lipids suggests a picture where the balance between two counterregulatory lipids (as shown in the particular example of ceramide and sphingosine-1-phosphate in T lymphocyte apoptosis) determines the cell fate by setting the stage for various protein signaling cascades. Here, we provide a further example of such a decisive balance composed of the two lipids sphingosine and sphingosine-1-phosphate that determines the allergic responsiveness of mast cells. High intracellular concentrations of sphingosine act as a potent inhibitor of the immunoglobulin (Ig)E plus antigen–mediated leukotriene synthesis and cytokine production by preventing activation of the mitogen-activated protein kinase pathway. In contrast, high intracellular levels of sphingosine-1-phosphate, also secreted by allergically stimulated mast cells, activate the mitogen-activated protein kinase pathway, resulting in hexosaminidase and leukotriene release, or in combination with ionomycin, give cytokine production. Equivalent high concentrations of sphingosine-1-phosphate are dominant over sphingosine as they counteract its inhibitory potential. Therefore, it might be inferred that sphingosine-kinase is pivotal to the activation of signaling cascades initiated at the Fcisin receptor I by modulating the balance of the counterregulatory lipids.

Key Words: mast cells • signal transduction • gene regulation

1used in this paper: BMMC, bone marrow–derived mouse mast cell; erk, extracellular signal regulatory kinase; jnk, c-jun NH2-terminal kinase; MAP, mitogen-activated protein; MAPK, MAP kinase; MBP, myelin basic protein; MEK, MAPK kinase; NF-AT, nuclear factor of activated T cell(s); PI-3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; RBL, rat basophilic leukemia; S, sphingosine; S1P, sphingosine-1-phosphate; SK, S-kinase

© 1999 The Rockefeller University Press


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