Sphingosine-1-phosphate receptor-2 mediated NF?B activation contributes to tumor necrosis factor-? induced VCAM-1 and ICAM-1 expression in endothelial cells.

ABSTRACT: Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions in endothelial cells. We previously showed that S1P receptor subtype 2 (S1P2) is significantly up-regulated in the atherosclerotic endothelium (J. Biol. Chem. 283:30363, 2008). In this study, we investigated the roles of S1P2-mediated signaling in the proinflammatory responses of endothelial cells. Treatment with tumor necrosis factor-? (TNF?), a proinflammatory cytokine, increased the expression of S1P2 receptors in endothelial cells. TNF? treatment also enhanced sphingosine kinase 1 expression and increased S1P production. Pharmacological inhibition or knockdown of S1P2 receptors completely abrogated the TNF?-induced VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) expression in endothelial cells. In contrast, pharmacological inhibition or knockdown of other S1P receptor subtypes had no effect on the TNF?-stimulated ICAM-1 and VCAM-1 expression. Moreover, ectopic expression of S1P2 receptors increased VCAM-1 and ICAM-1 expression in endothelial cells in response to S1P stimulation. Mechanistically, we show that antagonizing S1P2 signaling markedly inhibited the TNF?-stimulated NF?B activation. Utilizing the NF?B reporter luciferase assay, the S1P/S1P2 signaling was shown to stimulate NF?B activation. Moreover, the S1P/S1P2-stimulated VCAM-1/ICAM-1 expression was completely abolished by the pharmacological inhibitor of NF?B. Collectively, our data suggest that TNF? treatment activates autocrine S1P/S1P2 signaling, which subsequently activates NF?B and leads to the proinflammatory responses in endothelial cells.

SUBMITTER: Zhang W 

PROVIDER: S-EPMC3844125 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature