Journal article
Suppression of Ulcerative Colitis in Mice by Orally-Available Inhibitors of Sphingosine Kinase
Digestive diseases and sciences, Vol.53(4), pp.997-1012
04/2008
Handle:
https://hdl.handle.net/2376/107651
PMCID: PMC2660406
PMID: 18058233
Abstract
A critical step in the mechanism of action of inflammatory cytokines is the stimulation of sphingolipid metabolism, including activation of sphingosine kinase (SK) which produces the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). We have developed orally-bioavailable compounds that effectively inhibit SK activity
in vitro
, in intact cells and in cancer models
in vivo
. In the present study, we have assessed the effects of these SK inhibitors on cellular responses to TNFα, and evaluated their efficacies in the dextran sulfate sodium (DSS) model of ulcerative colitis in mice. Using several cell systems, it was shown that the SK inhibitors block the ability of TNFα to: activate NFκB; induce the expression of adhesion proteins; and promote the production of PGE
2
. In an acute model of DSS-induced ulcerative colitis, the SK inhibitors were equivalent to or more effective than Dipentum in reducing disease progression, colon shortening, and neutrophil infiltration into the colon. The effects of the SK inhibitors were associated with decreased colonic levels of the inflammatory cytokines TNFα, IL-1β, IFN-γ and IL-6, and reduction of S1P levels in the colon. A similar reduction in disease progression was provided by the SK inhibitors in a chronic model of ulcerative colitis in which the mice received three week-long cycles of DSS interspaced with week-long recovery periods. In the chronic model, immunohistochemistry for SK showed increased expression in DSS treated mice (compared to water controls) that was reduced by drug treatment. S1P levels were also elevated in the DSS group and significantly reduced by drug treatment. Together, these data indicate that SK is a critical component in inflammation, and that inhibitors of this enzyme may be useful in the treatment of inflammatory bowel diseases.
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Details
- Title
- Suppression of Ulcerative Colitis in Mice by Orally-Available Inhibitors of Sphingosine Kinase
- Creators
- Lynn W Maines - Apogee Biotechnology Corporation, Hershey, PALeo R Fitzpatrick - Department of Surgery, Penn State College of Medicine, Hershey, PAKevin J French - Apogee Biotechnology Corporation, Hershey, PAYan Zhuang - Apogee Biotechnology Corporation, Hershey, PAZuping Xia - Apogee Biotechnology Corporation, Hershey, PAStaci N Keller - Apogee Biotechnology Corporation, Hershey, PAJohn J Upson - Apogee Biotechnology Corporation, Hershey, PACharles D Smith - Apogee Biotechnology Corporation, Hershey, PA
- Publication Details
- Digestive diseases and sciences, Vol.53(4), pp.997-1012
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Identifiers
- 99900547252501842
- Language
- English
- Resource Type
- Journal article