The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fc epsilon receptor I triggering

Over the last few years, sphingolipids have been identified as potent secon d messenger molecules modulating cell growth and activation. A newly emergi ng facet to this class of lipids suggests a picture where the balance betwe en two counterregulatory lipids (as shown in the particular example of cera mide and sphingosine-l-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 t wo lipids sphingosine and sphingosine-l-phosphate that determines the aller gic responsiveness of mast cells. High intracellular concentrations of sphi ngosine act as a potent inhibitor of the immunoglobulin (Ig)E plus antigen- mediated leukotriene synthesis and cytokine production by preventing activa tion of the mitogen-activated protein kinase pathway. In contrast, high int racellular levels of sphingosine-1-phosphate, also secreted by allergically stimulated mast cells, activate the mitogen-activated protein kinase pathw ay, 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 i ts inhibitory potential. Therefore, it might be inferred that sphingosine-k inase is pivotal to the activation of signaling cascades initiated at the F c is an element of receptor I by modulating the balance of the counterregul atory lipids.