The Journal of Experimental Medicine
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Published 5 April 2004. doi:10.1084/jem.20030680
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 7, 959-970
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Transactivation of Sphingosine-1–Phosphate Receptors by Fc{varepsilon}RI Triggering Is Required for Normal Mast Cell Degranulation and Chemotaxis

Puneet S. Jolly1,2, Meryem Bektas1, Ana Olivera3, Claudia Gonzalez-Espinosa3, Richard L. Proia4, Juan Rivera3, Sheldon Milstien5, and Sarah Spiegel1

1 Department of Biochemistry, Virginia Commonwealth University Medical Center, Richmond, VA 23298
2 Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007
3 National Institute of Arthritis and Musculoskeletal and Skin Diseases, 4 National Institute of Diabetes and Digestive and Kidney Diseases, and 5 National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Sarah Spiegel, Dept. of Biochemistry, Virginia Commonwealth University Medical Center, Richmond, VA 23298. Phone: (804) 828-9330; Fax: (804) 828-8999; email: sspiegel{at}vcu.edu

Mast cells secrete various substances that initiate and perpetuate allergic responses. Cross-linking of the high-affinity receptor for IgE (Fc{varepsilon}RI) in RBL-2H3 and bone marrow–derived mast cells activates sphingosine kinase (SphK), which leads to generation and secretion of the potent sphingolipid mediator, sphingosine-1–phosphate (S1P). In turn, S1P activates its receptors S1P1 and S1P2 that are present in mast cells. Moreover, inhibition of SphK blocks Fc{varepsilon}RI-mediated internalization of these receptors and markedly reduces degranulation and chemotaxis. Although transactivation of S1P1 and Gi signaling are important for cytoskeletal rearrangements and migration of mast cells toward antigen, they are dispensable for Fc{varepsilon}RI-triggered degranulation. However, S1P2, whose expression is up-regulated by Fc{varepsilon}RI cross-linking, was required for degranulation and inhibited migration toward antigen. Together, our results suggest that activation of SphKs and consequently S1PRs by Fc{varepsilon}RI triggering plays a crucial role in mast cell functions and might be involved in the movement of mast cells to sites of inflammation.

Key Words: sphingosine kinase • S1P receptors • RBL-2H3 cells • motility

The online version of this article contains supplemental material.

Abbreviations used in this paper: ANOVA, analysis of variance; BMMC, bone marrow–derived mast cell; dihydro-S1P, S1P mimetic sphinganine-1–phosphate; DMS, N,N-dimethylsphingosine; EMEM, Eagle's minimal essential medium; Fc{varepsilon}RI, high-affinity receptor for IgE; GPCR, G protein–coupled receptor; GFP, green fluorescent protein; ICRAC, calcium release–activated calcium current; MCP-1, monocyte chemoattractant protein 1; MIP1, macrophage inflammatory protein 1; PTX, pertussis toxin; RPA, ribonuclease protection assay; S1P, sphingosine-1–phosphate; si, small interfering; SphK, sphingosine kinase; YFP, yellow fluorescent protein.


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