SEARCH:   Advanced

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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-03-011437v1 109/3/1077    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Payne, S. G. Articles by Spiegel, S. Search for Related Content PubMed PubMed Citation Articles by Payne, S. G. Articles by Spiegel, S. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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 FcRI-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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Lahiri, H. Park, E. L. Laviad, X. Lu, R. Bittman, and A. H. Futerman Ceramide Synthesis Is Modulated by the Sphingosine Analog FTY720 via a Mixture of Uncompetitive and Noncompetitive Inhibition in an Acyl-CoA Chain Length-de pend ent Manner J. Biol. Chem., June 12, 2009; 284(24): 16090 - 16098. [Abstract] [Full Text] [PDF] S.-C. Sensken, C. Bode, and M. H. Graler Accumulation of Fingolimod (FTY720) in Lymphoid Tissues Contributes to Prolonged Efficacy J. Pharmacol. Exp. Ther., March 1, 2009; 328(3): 963 - 969. [Abstract] [Full Text] [PDF] E. V. Berdyshev, I. Gorshkova, A. Skobeleva, R. Bittman, X. Lu, S. M. Dudek, T. Mirzapoiazova, J. G. N. Garcia, and V. Natarajan FTY720 Inhibits Ceramide Synthases and Up-regulates Dihydrosphingosine 1-Phosphate Formation in Human Lung Endothelial Cells J. Biol. Chem., February 27, 2009; 284(9): 5467 - 5477. [Abstract] [Full Text] [PDF] S. Sehrawat and B. T. Rouse Anti-Inflammatory Effects of FTY720 against Viral-Induced Immunopathology: Role of Drug-Induced Conversion of T Cells to Become Foxp3+ Regulators J. Immunol., June 1, 2008; 180(11): 7636 - 7647. [Abstract] [Full Text] [PDF] C. A. Oskeritzian, S. E. Alvarez, N. C. Hait, M. M. Price, S. Milstien, and S. Spiegel Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions Blood, April 15, 2008; 111(8): 4193 - 4200. [Abstract] [Full Text] [PDF] C. A. Foster, L. M. Howard, A. Schweitzer, E. Persohn, P. C. Hiestand, B. Balatoni, R. Reuschel, C. Beerli, M. Schwartz, and A. Billich Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 469 - 475. [Abstract] [Full Text] [PDF] R. P. Coelho, S. G. Payne, R. Bittman, S. Spiegel, and C. Sato-Bigbee The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 626 - 635. [Abstract] [Full Text] [PDF] Y. Kurashima, J. Kunisawa, M. Higuchi, M. Gohda, I. Ishikawa, N. Takayama, M. Shimizu, and H. Kiyono Sphingosine 1-Phosphate-Mediated Trafficking of Pathogenic Th2 and Mast Cells for the Control of Food Allergy J. Immunol., August 1, 2007; 179(3): 1577 - 1585. [Abstract] [Full Text] [PDF]

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020