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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1454-1458. Prepublished online as a Blood First Edition Paper on October 13, 2005; DOI 10.1182/blood-2005-07-2628. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-07-2628v1 107/4/1454    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 Zemann, B. Articles by Billich, A. Search for Related Content PubMed PubMed Citation Articles by Zemann, B. Articles by Billich, A. Related Collections Immunobiology Transplantation Signal Transduction Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720 Barbara Zemann, Bernd Kinzel, Matthias Müller, Roland Reuschel, Diana Mechtcheriakova, Nicole Urtz, Frédéric Bornancin, Thomas Baumruker, and Andreas Billich From the Novartis Institutes for BioMedical Research, Vienna, Austria, and Basel, Switzerland. FTY720, a potent immunomodulatory drug in phase 2/3 clinical trials, induces rapid and reversible sequestration of lymphocytes into secondary lymphoid organs, thereby preventing their migration to sites of inflammation. As prerequisite for its function, phosphorylation of FTY720 to yield a potent agonist of the sphingosine-1-phosphate receptor S1P1 is required in vivo, catalyzed by an as-yet-unknown kinase. Here, we report on the generation of sphingosine kinase 2 (SPHK2) knockout mice and demonstrate that this enzyme is essential for FTY720 phosphate formation in vivo. Consequently, administration of FTY720 does not induce lymphopenia in SPHK2-deficient mice. After direct dosage of FTY720 phosphate, lymphopenia is only transient in this strain, indicating that SPHK2 is constantly required to maintain FTY720 phosphate levels in vivo. 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] J. S. Karliner Sphingosine kinase regulation and cardioprotection Cardiovasc Res, May 1, 2009; 82(2): 184 - 192. [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] T. Kawamori, T. Kaneshiro, M. Okumura, S. Maalouf, A. Uflacker, J. Bielawski, Y. A. Hannun, and L. M. Obeid Role for sphingosine kinase 1 in colon carcinogenesis FASEB J, February 1, 2009; 23(2): 405 - 414. [Abstract] [Full Text] [PDF] O. Coste, C. Brenneis, B. Linke, S. Pierre, C. Maeurer, W. Becker, H. Schmidt, W. Gao, G. Geisslinger, and K. Scholich Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing J. Biol. Chem., November 21, 2008; 283(47): 32442 - 32451. [Abstract] [Full Text] [PDF] D. Marsolais, B. Hahm, K. H. Edelmann, K. B. Walsh, M. Guerrero, Y. Hatta, Y. Kawaoka, E. Roberts, M. B. A. Oldstone, and H. Rosen Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza Mol. Pharmacol., September 1, 2008; 74(3): 896 - 903. [Abstract] [Full Text] [PDF] K. Takabe, S. W. Paugh, S. Milstien, and S. Spiegel "Inside-Out" Signaling of Sphingosine-1-Phosphate: Therapeutic Targets Pharmacol. Rev., June 1, 2008; 60(2): 181 - 195. [Abstract] [Full Text] [PDF] K. Venkataraman, Y.-M. Lee, J. Michaud, S. Thangada, Y. Ai, H. L. Bonkovsky, N. S. Parikh, C. Habrukowich, and T. Hla Vascular Endothelium As a Contributor of Plasma Sphingosine 1-Phosphate Circ. Res., March 28, 2008; 102(6): 669 - 676. [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] N. C. Hait, A. Bellamy, S. Milstien, T. Kordula, and S. Spiegel Sphingosine Kinase Type 2 Activation by ERK-mediated Phosphorylation J. Biol. Chem., April 20, 2007; 282(16): 12058 - 12065. [Abstract] [Full Text] [PDF] R. Pappu, S. R. Schwab, I. Cornelissen, J. P. Pereira, J. B. Regard, Y. Xu, E. Camerer, Y.-W. Zheng, Y. Huang, J. G. Cyster, et al. Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate Science, April 13, 2007; 316(5822): 295 - 298. [Abstract] [Full Text] [PDF] P. Hanel, P. Andreani, and M. H. Graler Erythrocytes store and release sphingosine 1-phosphate in blood FASEB J, April 1, 2007; 21(4): 1202 - 1209. [Abstract] [Full Text] [PDF] C. Nombela-Arrieta, T. R. Mempel, S. F. Soriano, I. Mazo, M. P. Wymann, E. Hirsch, C. Martinez-A., Y. Fukui, U. H. von Andrian, and J. V. Stein A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress J. Exp. Med., March 19, 2007; 204(3): 497 - 510. [Abstract] [Full Text] [PDF] C. D. Keller, P. Rivera Gil, M. Tolle, M. van der Giet, J. Chun, H. H. Radeke, M. Schafer-Korting, and B. 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