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A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis

Ashley J. Snider^*, Toshihiko Kawamori, Sarah G. Bradshaw^||, K. Alexa Orr, Gary S. Gilkeson^||, Yusuf A. Hannun and Lina M. Obeid^1,*,,||

^* Department of Medicine,

Department of Pathology and Laboratory Medicine,

Department of Molecular and Cellular Biology and Pathobiology, and

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA; and

^|| Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA

¹ Correspondence: Department of Medicine, Medical University of South Carolina, 114 Doughty St., MSC 779, Charleston, SC 29425, USA. E-mail: obeidl{at}musc.edu

The bioactive lipid sphingosine-1-phosphate (S1P) is emerging as an important mediator of immune and inflammatory responses. S1P formation is catalyzed by sphingosine kinase (SK), of which the SK1 isoenzyme is activated by tumor necrosis alpha (TNF-). SK1 has been shown to be required for mediating TNF- inflammatory responses in cells, including induction of cyclooxygenase 2 (COX-2). Because TNF- and COX-2 are increased in patients with inflammatory bowel disease (IBD), we investigated the role of SK1 in a murine model of colitis. SK1^–/– mice treated with dextran sulfate sodium (DSS) had significantly less blood loss, weight loss, colon shortening, colon histological damage, and splenomegaly than did wild-type (WT) mice. In addition, SK1^–/– mice had no systemic inflammatory response. Moreover, WT but not SK1^–/– mice treated with dextran sulfate sodium had significant increases in blood S1P levels, colon SK1 message and activity, and colon neutrophilic infiltrate. Unlike WT mice, SK1^–/– mice failed to show colonic COX-2 induction despite an exaggerated TNF- response; thus implicating for the first time SK1 in TNF--mediated COX-2 induction in vivo. Inhibition of SK1 may prove to be a valuable therapeutic target by inhibiting systemic and local inflammation in IBD.—Snider, A. J., Kawamori, T., Bradshaw, S. G., Orr, K. A., Gilkeson, G. S., Hannun, Y. A., Obeid, L. M. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis.

Key Words: sphingosine-1-phosphate • tumor necrosis factor alpha • cyclooxygenase-2 • inflammation • ceramide

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				M. Maceyka, S. Milstien, and S. Spiegel Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling J. Lipid Res., April 1, 2009; 50(Supplement): S272 - S276. [Abstract] [Full Text] [PDF]