title: Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A-1235 Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zemann
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.forename: Roland
authors.initials: R
authors.lastname: Reuschel
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.forename: Nicole
authors.initials: N
authors.lastname: Urtz
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bornancin
authors.forename: Thomas
authors.initials: T
authors.lastname: Baumruker
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D010710:Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D012333:RNA, Messenger; D013110:Sphingosine; D000099157:Sphingosine Kinase