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Sphingosine-1-Phosphate Prevents Tumor Necrosis Factor-α–Mediated Monocyte Adhesion to Aortic Endothelium in Mice

2005; Lippincott Williams & Wilkins; Volume: 25; Issue: 5 Linguagem: Inglês

10.1161/01.atv.0000162171.30089.f6

1524-4636

David T. Bolick, Suseela Srinivasan, Kyu W. Kim, Melissa E. Hatley, Jeremy J. Clemens, Angela M. Whetzel, Nicole Ferger, Timothy L. Macdonald, Michael D. Davis, Philip S. Tsao, Kevin R. Lynch, Catherine C. Hedrick,

Lipid Membrane Structure and Behavior

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.