Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells

Sphingosine l-phosphate (SlP) stimulates expression of vascular cell adhesion molecule-1 and intercellular adhesion rnolecule-1 in human umbilical vein endothelial cells. SlP-induced actions were associated with nuclear factor kappa-B activation and inhibited by pertussis toxin as well as by antisense oligonucleotides specific to SlP receptors, especially, SlP(3). SlP also stimulated endothelial nitric oxide synthase (eNOS) and its activation was markedly inhibited by the antisense oligonucleotide for the SlP, receptor rather than that for the SlP3 receptor. The dose-response curve of SlP to stimulate adhesion molecule expression was shifted to the left in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin and the NOS inhibitor N omega-nitro-L-arginine methyl ester. NO donor S-nitroso-N-acetylpenicillamine inhibited SIP-induced adhesion molecule expression. Moreover, tumor necrosis factor-alpha-induced adhesion molecule expression was markedly inhibited by SlP in a manner sensitive to inhibitors for PI3-K and NOS. These results suggest that SlP receptors are coupled to both stimulatory and inhibitory pathways for adhesion molecule expression. The stimulatory pathway involves nuclear factor kappa-B and inhibitory one does phosphatidylinositol 3-kinase and NOS. (c) 2005 Elsevier Inc. All rights reserved.