Dual action of sphingosine 1-phosphate in eliciting proinflammatory responses in primary cultured rat intestinal smooth muscle cells.

Sphingosine 1-phosphate (S1P) is involved in the local inflammatory response within the intestinal muscularis, which has been suggested to play a major role in the pathogenesis of postoperative ileus. The aim of the present study was to elucidate the role of S1P and the molecular mechanisms underlying regulation of inflammatory mediators in primary cultured rat intestinal smooth muscle (RISM) cells. Although our experimental data clearly show the mediatory role of sphingosine kinase (SK)-derived S1P in the TNF-alpha and the LPS induced activation of NF-kB, exogenously added S1P failed to trigger this transcription factor.

Specificity of the dihydroceramide desaturase inhibitor N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11) in primary cultured cerebellar neurons.

Dihydroceramide desaturase catalyzes the conversion of the innocuous precursor dihydroceramide into a highly bioactive product ceramide. We studied the effect of N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first inhibitor of this enzyme, in primary cultured cerebellar neurons. Although desaturase was efficiently inhibited (IC50 of 23 nM), the compound lost its specificity at higher concentrations.