Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720.
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.
Zemann
Barbara
B
Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A-1235 Vienna, Austria.
Kinzel
Bernd
B
Müller
Matthias
M
Reuschel
Roland
R
Mechtcheriakova
Diana
D
Urtz
Nicole
N
Bornancin
Frédéric
F
Baumruker
Thomas
T
Billich
Andreas
A
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
D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D010710:Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D012333:RNA, Messenger; D013110:Sphingosine; D000099157:Sphingosine Kinase