Sphingosine-1-phosphate prevents tumor necrosis factor-α-mediated monocyte adhesion to aortic endothelium in mice

Objective - Endothelial activation and monocyte adhesion to endothelium are key events in inflammation. Sphingosine-1-phosphate (S1P) is a sphingolipid that binds to G protein-coupled receptors on endothelial cells (ECs). We examined the role of S1P in modulating endothelial activation and monocyte-EC interactions in vivo. Methods and Results - We injected C57BL/6J mice intravenously with tumor necrosis factor (TNF)-α in the presence and absence of the S1P1 receptor agonist SEW2871 and examined monocyte adhesion. Aortas from TNF-α-injected mice had a 4-fold increase in the number of monocytes bound, whereas aortas from TNF-α plus SEW2871-treated mice had few monocytes bound (P<0.0001). Using siRNA, we found that inhibiting the S1P1 receptor in vascular ECs blocked the ability of S1P to prevent monocyte-EC interactions in response to TNF-α. We examined signaling pathways downstream of S1P1 and found that 100 nM S1P increased phosphorylation of Akt and decreased activation of c-jun. Conclusions - Thus, we provide the first evidence that S1P signaling through the endothelial S1P1 receptor protects the vasculature against TNF-α-mediated monocyte-EC interactions in vivo.