The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors
- 28 September 2006
- journal article
- Published by American Society of Hematology in Blood
- Vol. 109 (3), 1077-1085
- https://doi.org/10.1182/blood-2006-03-011437
Abstract
FTY720 is a potent immunomodulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate, which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. However, in contrast to S1P, FTY720 has no effect on mast-cell degranulation, yet significantly reduces antigen-induced secretion of PGD2 and cysteinyl-leukotriene. Unexpectedly, this effect of FTY720 was independent of its phosphorylation and S1P receptor functions. The rate-limiting step in the biosynthesis of all eicosanoids is the phospholipase A2 (PLA2)–mediated release of arachidonic acid from glycerol phospholipids. Although FTY720 also reduced arachidonic acid release in response to antigen, it had no effect on translocation of cPLA2 or ERK1/2 activation, suggesting that it does not interfere with FcϵRI-mediated events leading to cPLA2 activation. Remarkably, however, FTY720 drastically inhibited recombinant cPLA2α activity, whereas FTY720-phosphate, sphingosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA2α and hence on production of all eicosanoids. Our results have important implications for the potential therapeutic mechanism of action of FTY720 in eicosanoid-driven inflammatory disorders such as asthma and multiple sclerosis.Keywords
This publication has 70 references indexed in Scilit:
- IgE-dependent Activation of Sphingosine Kinases 1 and 2 and Secretion of Sphingosine 1-Phosphate Requires Fyn Kinase and Contributes to Mast Cell ResponsesPublished by Elsevier BV ,2006
- Signals for lymphocyte egress.Nature Immunology, 2005
- Dihydrosphingosine 1‐phosphate stimulates MMP1 gene expression via activation of ERK1/2‐Ets1 pathway in human fibroblastsThe FASEB Journal, 2005
- Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinusesNature Immunology, 2005
- Sphingosine 1-phosphate and its receptors: an autocrine and paracrine networkNature Reviews Immunology, 2005
- The Coordination of Prostaglandin E2 Production by Sphingosine-1-phosphate and Ceramide-1-phosphateMolecular Pharmacology, 2005
- CHEMOKINES, SPHINGOSINE-1-PHOSPHATE, AND CELL MIGRATION IN SECONDARY LYMPHOID ORGANSAnnual Review of Immunology, 2005
- The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate ReceptorsPublished by Elsevier BV ,2002
- Tumour necrosis factor‐α: The role of this multifunctional cytokine in asthmaImmunology & Cell Biology, 2001
- cPLA2 is phosphorylated and activated by MAP kinaseCell, 1993