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

FTY720 is a potent immunomodulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FTY720 is phosphorylated in vivo by sphin-gosine 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 func-tions. The rate-limiting step in the biosyn-thesis of all eicosanoids is the phospho-lipase A2 (PLA2)–mediated release of arachidonic acid from glycerol phospho-lipids. Although FTY720 also reduced ara-chidonic acid release in response to anti-gen, it had no effect on translocation of cPLA2 or ERK1/2 activation, suggesting that it does not interfere with FcRI-mediated events leading to cPLA2 activa-tion. Remarkably, however, FTY720 dras-tically inhibited recombinant cPLA2 activity, whereas FTY720-phosphate, sphin-gosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA2 and hence on produc-tion of all eicosanoids. Our results have important implications for thepotential thera-peutic mechanism of action of FTY720 in eicosanoid-driven inflammatory disorders such as asthma and multiple sclerosis