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 Blood, 15 April 2008, Vol. 111, No. 8, pp. 4193-4200.
Prepublished online as a Blood First Edition Paper on January 4, 2008; DOI 10.1182/blood-2007-09-115451.

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IMMUNOBIOLOGY

Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

Carole A. Oskeritzian1, Sergio E. Alvarez1, Nitai C. Hait1, Megan M. Price1, Sheldon Milstien2, and Sarah Spiegel1

1 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond; and 2 National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD

Sphingosine-1-phosphate (S1P) is now emerging as a potent lipid mediator produced by mast cells that contributes to inflammatory and allergic responses. In contrast to its weak effect on degranulation of murine mast cells, S1P potently induced degranulation of the human LAD2 mast-cell line and cord blood–derived human mast cells (hMCs). S1P also stimulated production and secretion of cytokines, TNF-{alpha} and IL-6, and markedly enhanced secretion of a chemokine, CCL2/MCP-1, important modulators of inflammation. S1P is produced in mast cells by the 2 sphingosine kinases, SphK1 and SphK2. SphK1 but not SphK2 plays a critical role in IgE/Ag-induced degranulation, migration toward antigen, and CCL2 secretion from hMCs, as determined by specifically down-regulating their expression. However, both isoenzymes were required for efficient TNF-{alpha} secretion. Taken together, our data suggest that differential formation of S1P by SphK1 and SphK2 has distinct and important actions in hMCs.


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