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A Novel Function of the Immunosuppressant Drug FTY720 Independent of Its Phosphorylation as a Direct Cytosolic Phospholipase A2 Inhibitor
Author(s) -
Spiegel Sarah,
Payne Shawn G,
Oskeritzian Carole A,
Griffiths Rachael,
Subramanian Pretti,
Barbour Suzanne E,
Chalfant Charles E
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a849-b
Subject(s) - degranulation , sphingosine , mast cell , sphingosine kinase , lipid signaling , leukotriene c4 , leukotriene , eicosanoid , receptor , chemistry , sphingosine 1 phosphate receptor , phosphorylation , sphingosine 1 phosphate , biology , microbiology and biotechnology , pharmacology , biochemistry , arachidonic acid , immunology , enzyme , asthma
FTY720 is a potent immunomudulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720‐P, which acts as a potent sphingosine‐1‐phosphate (S1P) receptor agonist. We have previously shown that S1P and S1P receptors are required for mast cell functions, including degranulation and migration to sites of inflammation. In this study, we investigated the effects of S1P and FTY720 on antigen‐stimulated release of inflammatory mediators by mast cells. FTY720, in contrast to S1P, had no effect on mast cell degranulation. Yet preincubation of rat basophilic leukemia cells (RBL‐2H3) and LAD2 human mast cells with FTY720 significantly reduced antigen‐induced eicosanoid (PGD 2 and cysteinyl‐leukotriene) secretion. Unexpectedly, this effect was independent of its phosphorylation and S1P receptor functions as neither S1P nor FTY720‐P or SEW8271, a selective S1P 1 receptor agonist, significantly affected PGD 2 and cysteinyl‐leukotriene secretion. FTY720 reduced release of arachidonic acid in response to antigen and markedly inhibited recombinant cPLA 2 activity in a mixed micelle assay, whereas FTY720‐P, sphingosine, or S1P had no effects. Thus, we have uncovered a unique action of FTY720 as a direct inhibitor of cPLA 2 the rate‐limiting enzyme in eicosanoid formation.