Sphingosine 1-phosphate (S1P) induces expression of E-selectin and adhesion of monocytes via intracellular signalling pathways in vascular endothelial cells.

Sphingosine 1-phosphate (S1P) - a constitutive component of human plasma - is implicated as a signalling molecule in the regulation of cell adhesion molecules (CAM) in vascular endothelial cells (EC), but the degree of the S1P-induced expression of CAM and the involvement of the S1P(1) receptor are still ambiguous. Here, we report that S1P, when added to vascular EC in the absence of other stimuli, induced a strictly proportional and concentration-dependent expression of E-selectin mRNA, of E-selectin protein and of the number of adhering THP-1 monocytes to EC. Experiments with exogenous [(3)H]S1P showed a multi-exponential influx kinetic of intracellular uptake of [(3)H]S1P up to a steady state level over 2h. This process could be inhibited or enhanced by various synthetic modulators targeting both, S1P(1) receptor-dependent (Akt, ERK1/2) as well as independent DMS-sensitive pathways. The S1P(1) receptor signalling was shown to drive the sphingosine kinase - the rate limiting enzyme for the formation of S1P - to a higher or lower activity. Furthermore, S1P as an intracellular messenger induced the phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB and in turn the expression of E-selectin and monocyte adhesion. Taken together, these results suggest that the physiologically controlled variation in intracellular S1P concentrations may represent a novel not yet known mechanism of fine-tuning the expression of proinflammatory and atherogenic E-selectin cell adhesion molecule by vascular endothelial cells.