Sphingosine 1-phosphate (S1P) levels are significantly higher in blood and lymph than in tissues. This S1P concentration difference is necessary for proper lymphocyte egress from secondary lymphoid tissue and to maintain endothelial barrier integrity. In the present study, all SphK inhibitors tested decrease S1P when applied to cultured U-937 cells, only those inhibitors with a bias for SphK2 drove a substantial increase in blood S1P in mice and this rise was detectable within minutes of drug administration. Mass labeled S1P was cleared more slowly after intravenous injection into SphK2 inhibitor treated mice or in mice lacking a functional SphK2 gene, thus the increased accumulation of S1P in the blood of appears to result from the decreased clearance of S1P from blood. Therefore SphK2 appears to have a function independent of generating S1P in cells. These results suggest that differential SphK inhibition with a drug might afford a method to manipulate blood S1P levels in either direction while lowering tissue S1P levels.
See article at J Pharmacol Exp Ther 2015 355:23-31.
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