title: Sphingosine kinase 2 deficient mice exhibit reduced experimental autoimmune encephalomyelitis: Resistance to FTY720 but not ST-968 treatments.
abstract: The immunomodulatory drug FTY720 is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that requires activation by sphingosine kinase 2 (SK-2) to induce T cell homing to secondary lymphoid tissue. In this study, we have investigated the role of SK-2 in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. We show that SK-2 deficiency reduced clinical symptoms of EAE. Furthermore, in SK-2-deficient mice, the protective effect of FTY720 on EAE was abolished, while the non-prodrug FTY720-derivative ST-968 was still fully active. Protection was paralleled by reduced numbers of T-lymphocytes in blood and a reduced blood-brain-barrier leakage. This correlated with reduced mRNA expression of ICAM-1, VCAM-1, but enhanced expression of PECAM-1. A similar regulation of permeability and of PECAM-1 was seen in primary cultures of isolated mouse brain vascular endothelial cells and in a human immortalized cell line upon SK-2 knockdown. In summary, these data demonstrated that deletion of SK-2 exerts a protective effect on the pathogenesis of EAE in C57BL/6 mice and that SK-2 is essential for the protective effect of FTY720 but not of ST-968. Thus, ST-968 is a promising novel immunomodulatory compound that may be a valuable alternative to FTY720 under conditions where SK-2 activity is limited.
authors.affiliation: Institute of Pharmacology, University of Bern, Inselspital INO-F, CH-3010 Bern, Switzerland.
authors.forename: Faik
authors.initials: F
authors.lastname: Imeri
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schwalm
authors.affiliation: Theodor-Kocher Institute, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zivkovic
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Theodor-Kocher Institute, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.affiliation: Institute of Pharmacology, University of Bern, Inselspital INO-F, CH-3010 Bern, Switzerland. Electronic address: Huwiler@pki.unibe.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D055785:Gene Knockdown Techniques; D007155:Immunologic Factors / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D010080:Oxazoles / Q000627:therapeutic use*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D007155:Immunologic Factors; D018799:Intercellular Adhesion Molecule-1; D010080:Oxazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; C000596158:7a-(4-octylphenethyl)tetrahydro-1H-oxazolo(3,4-c)oxazole; C090509:Icam1 protein, mouse; C000603447:sphingosine kinase 2, mouse; D000099157:Sphingosine Kinase
keywords: Blood-brain-barrier; Endothelial cells; Experimental autoimmune encephalomyelitis; FTY720; ST-968; Sphingosine kinase 2