Abstract
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)-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.
Conclusions:
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aorta / cytology
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Aorta / immunology
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Cell Adhesion / drug effects*
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Cell Adhesion / immunology
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Cells, Cultured
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Chemokines / metabolism
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E-Selectin / metabolism
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Endothelium, Vascular / cytology*
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Endothelium, Vascular / immunology
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Intercellular Adhesion Molecule-1 / metabolism
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Lysophospholipids / pharmacology*
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Mice
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Mice, Inbred C57BL
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Monocytes / cytology*
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Monocytes / immunology
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Oxadiazoles / pharmacology
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Receptors, Lysosphingolipid / agonists
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Receptors, Lysosphingolipid / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Thiophenes / pharmacology
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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Vascular Cell Adhesion Molecule-1 / metabolism
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Vasculitis / drug therapy*
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Vasculitis / metabolism
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Vasculitis / prevention & control
Substances
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Chemokines
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E-Selectin
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Lysophospholipids
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Oxadiazoles
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Receptors, Lysosphingolipid
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SEW2871
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Thiophenes
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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sphingosine 1-phosphate
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Sphingosine