Dataset Information

Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages.

ABSTRACT: Sphingosine kinase 1 (SK1) and its product sphingosine-1-phosphate (S1P) have been implicated in the regulation of many cellular processes including growth regulation, protection from apoptosis, stimulation of angiogenesis, and most recently as mediators of the TNF-alpha inflammatory response. In this study we set out to examine the role of SK1/S1P in the RAW macrophage response to the potent inflammatory stimulus lipopolysaccharide (LPS). We show that LPS increases cellular levels of SK1 message and protein. This increase is at the transcriptional level and is accompanied by increased SK activity and generation of S1P. S1P is able to cause increases in COX-2 and PGE2 levels in RAW cells. Knockdown of SK1 using siRNA is able to inhibit the TNF but not the LPS inflammatory response. Moreover, knockdown of SK1 enhances both TNF- and LPS-induced apoptosis. These data indicate that there is a dual and distinct role for SK1 and S1P in the TNF and the LPS inflammatory pathways.

SUBMITTER: Hammad SM

PROVIDER: S-EPMC2290737 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages.

Hammad Samar M SM Crellin Heather G HG Wu Bill X BX Melton Jessica J Anelli Viviana V Obeid Lina M LM

Prostaglandins & other lipid mediators 20071124 3-4

Sphingosine kinase 1 (SK1) and its product sphingosine-1-phosphate (S1P) have been implicated in the regulation of many cellular processes including growth regulation, protection from apoptosis, stimulation of angiogenesis, and most recently as mediators of the TNF-alpha inflammatory response. In this study we set out to examine the role of SK1/S1P in the RAW macrophage response to the potent inflammatory stimulus lipopolysaccharide (LPS). We show that LPS increases cellular levels of SK1 messag ...[more]

PMID: 18166496

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Project description:Activated macrophages acquire a proinflammatory (classic) or antiinflammatory (alternative) phenotype that influences atherosclerosis. The present study investigated whether sphingosine-1-phosphate (S1P), with its known antiinflammatory effects, could regulate the inflammatory phenotype of lipopolysaccharide (LPS)-stimulated mouse macrophages. Activation of macrophages by LPS significantly increases proinflammatory cytokine secretion. Pretreatment of macrophages with 500 nmol/L S1P markedly reduced LPS-mediated secretion of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin-12. Such antiinflammatory actions were also evident in LPS-stimulated macrophages treated with the S1P1 receptor-specific agonist SEW2871. Pharmacological antagonism of the S1P1 receptor on macrophages using the S1P1-specific antagonist VPC44116 also blocked proinflammatory cytokine secretion in response to LPS. Studies using bone marrow-derived macrophages from S1P2-deficient mice revealed that the S1P2 receptor did not play a pivotal role in this process. Thus, activation of the S1P1 receptor in mouse macrophages limits the expression of proinflammatory cytokines. Furthermore, we demonstrated that S1P increased arginase I activity and inhibited LPS-induced inducible NO synthase activity in LPS-treated macrophages, again through S1P1 receptor activation on macrophages. Analysis of a 1.7-kb region of the murine inducible NO synthase promoter revealed the presence of putative nuclear factor kappaB, activator protein-1, and STAT-1 response elements. Using inducible NO synthase promoter-reporter constructs, we found that S1P significantly reduced the nuclear factor kappaB-mediated induction of inducible NO synthase. These findings demonstrate an important role for S1P in the regulation of macrophage phenotypic switching. Therefore, we conclude that S1P promotes the production of an alternative antiinflammatory macrophage phenotype through activation of the macrophage S1P1 receptor.

Dataset Information

Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages.

Publications

Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages.

Similar Datasets

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