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.