The immunosuppressant drug FTY720 inhibits cytosohc phospholipase A2 independently of sphingosine-1-phosphate receptors

FrY720 is a potent immunomodulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FrY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate, which acts as a potent sphingosine-1-phosphate (SI P) receptor agonist. However, in contrast to S1P, FTY720 has no effect on mast-cell degranulation, yet significantly reduces antigen-induced secretion of PGD(2) and cysteinyl-leukotriene. Unexpectedly, this effect of FTY720 was independent of its phosphorylation and S1P receptor functions. The rate-limiting step in the blosynthesis of all elcosanolds is the phospholipase A(2) (PLA(2))-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 cPLA(2) or ERK1/2 activation, suggesting that it does not interfere with Fc epsilon RI-mediated events leading to cPLA2 activation. Remarkably, however, FTY720 drastically inhibited recombinant cPLA(2)alpha activity, whereas FrY720-phosphate, sphin-gosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA(2)alpha and hence on production of all eicosanoids. Our results have important implications for the potential therapeutic mechanism of action of FrY720 in eicosanold-driven inflammatory disorders such as asthma and multiple sclerosis.