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Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720.

Zemann, Barbara and Kinzel, Bernd and Mueller, Matthias and Reuschel, Roland and Mechtcheriakova, Diana and Urtz, Nicole and Bornancin, Frederic and Baumruker, Thomas and Billich, Andreas (2006) Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood, 107 (4). pp. 1454-1458. ISSN 0006-4971

Abstract

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 S1P(1) 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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author's personal web site or On departmental web site
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Date Deposited: 14 Dec 2009 13:59
Last Modified: 31 Jan 2013 01:15
URI: https://oak.novartis.com/id/eprint/493

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