sew2871 and Vasculitis

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.. We injected C57BL/6J mice intravenously with tumor necrosis factor (TNF)-alpha in the presence and absence of the S1P1 receptor agonist SEW2871 and examined monocyte adhesion. Aortas from TNF-alpha-injected mice had a 4-fold increase in the number of monocytes bound, whereas aortas from TNF-alpha 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-alpha. We examined signaling pathways downstream of S1P1 and found that 100 nM S1P increased phosphorylation of Akt and decreased activation of c-jun.. Thus, we provide the first evidence that S1P signaling through the endothelial S1P1 receptor protects the vasculature against TNF-alpha-mediated monocyte-EC interactions in vivo.

Topics: Animals; Aorta; Cell Adhesion; Cells, Cultured; Chemokines; E-Selectin; Endothelium, Vascular; Intercellular Adhesion Molecule-1; Lysophospholipids; Mice; Mice, Inbred C57BL; Monocytes; Oxadiazoles; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Thiophenes; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vasculitis