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Suppression of Ulcerative Colitis in Mice by Orally Available Inhibitors of Sphingosine Kinase
- Source :
- Digestive Diseases and Sciences. 53:997-1012
- Publication Year :
- 2007
- Publisher :
- Springer Science and Business Media LLC, 2007.
-
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 proinflammatory 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 this study, we assessed the effects of these SK inhibitors on cellular responses to tumor necrosis factor alpha (TNFalpha) and evaluated their efficacy 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 TNFalpha to activate nuclear factor kappa B (NFkappaB), induce expression of adhesion proteins, and promote production of prostaglandin E(2) (PGE(2)). In an acute model of DSS-induced ulcerative colitis, 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 SK inhibitors were associated with decreased colonic levels of inflammatory cytokines TNFalpha, interleukin (IL)-1beta, interferon gamma (IFN)-gamma, IL-6, and reduction of S1P levels. A similar reduction in disease progression was provided by SK inhibitors in a chronic model of ulcerative colitis in which the mice received 3-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 with water-treated 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 treating inflammatory bowel diseases.
- Subjects :
- Male
medicine.medical_specialty
Physiology
medicine.medical_treatment
Sphingosine kinase
Administration, Oral
Pharmacology
Inflammatory bowel disease
Article
Proinflammatory cytokine
Mice
chemistry.chemical_compound
Internal medicine
medicine
Animals
Interferon gamma
Colitis
Sphingosine
Tumor Necrosis Factor-alpha
business.industry
Dextran Sulfate
NF-kappa B
Gastroenterology
medicine.disease
digestive system diseases
Mice, Inbred C57BL
Disease Models, Animal
Phosphotransferases (Alcohol Group Acceptor)
Endocrinology
Cytokine
chemistry
Cytokines
Colitis, Ulcerative
Tumor necrosis factor alpha
business
medicine.drug
Subjects
Details
- ISSN :
- 15732568 and 01632116
- Volume :
- 53
- Database :
- OpenAIRE
- Journal :
- Digestive Diseases and Sciences
- Accession number :
- edsair.doi.dedup.....a74d1758c6f161288f1dd5ab2524fa57