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, Lina M. Obeid

Research output: Contribution to journalArticlepeer-review

160 Scopus citations

Abstract

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-α). SK1 has been shown to be required for mediating TNF-α inflammatory responses in cells, including induction of cyclooxygenase 2 (COX-2). Because TNF-α 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-α response; thus implicating for the first time SK1 in TNF-α-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.

Original languageEnglish (US)
Pages (from-to)143-152
Number of pages10
JournalFASEB Journal
Volume23
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

Keywords

  • Ceramide
  • Cyclooxygenase-2
  • Inflammation
  • Sphingosine-1-phosphate
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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