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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1077-1085.
Prepublished online as a Blood First Edition Paper on September 28, 2006; DOI 10.1182/blood-2006-03-011437.
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IMMUNOBIOLOGY
The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors
Shawn G. Payne1,
Carole A. Oskeritzian1,
Rachael Griffiths1,
Preeti Subramanian1,
Suzanne E. Barbour1,
Charles E. Chalfant1,
Sheldon Milstien2, and
Sarah Spiegel1
1 Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA; and
2 National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD
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 Fc RI-mediated events leading to cPLA2 activation. Remarkably, however, FTY720 drastically inhibited recombinant cPLA2 activity, whereas FTY720-phosphate, sphingosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA2 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.
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