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

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• 作者：Wenliang Zhang ; Jin An ; Hiba Jawadi ; Deanna L. Siow ; Jen-Fu Lee ; Jiawei Zhao ; Allison Gartung ; Krishna Rao Maddipati ; Kenneth V. Honn ; Binks W. Wattenberg ; Menq-Jer Lee
• 关键词：S1P ; sphingosine-1-phosphate ; GPCR ; G-protein coupled receptor ; S1P1&ndash ; 5 ; high affinity GPCRs for S1P ; TNF伪 ; tumor necrosis factor-伪 ; VCAM-1 ; vascular cell adhesion molecule 1 ; ICAM-1 ; intercellular adhesion molecule 1 ; SphK ; sphingosine kinase ; HUVEC ; human umbilical vein endothelial cells ; ECs ; cultured endothelial cells
• 刊名：Prostaglandins and Other Lipid Mediators
• 出版年：October, 2013
• 年：2013
• 卷：106
• 期：Complete
• 页码：62-71
• 全文大小：1649 K

文摘

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-伪 (TNF伪), a proinflammatory cytokine, increased the expression of S1P₂ receptors in endothelial cells. TNF伪 treatment also enhanced sphingosine kinase 1 expression and increased S1P production. Pharmacological inhibition or knockdown of S1P₂ receptors completely abrogated the TNF伪-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伪-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伪-stimulated NF魏B activation. Utilizing the NF魏B reporter luciferase assay, the S1P/S1P₂ signaling was shown to stimulate NF魏B activation. Moreover, the S1P/S1P₂-stimulated VCAM-1/ICAM-1 expression was completely abolished by the pharmacological inhibitor of NF魏B. Collectively, our data suggest that TNF伪 treatment activates autocrine S1P/S1P₂ signaling, which subsequently activates NF魏B and leads to the proinflammatory responses in endothelial cells.