TLR-4 and Sustained Calcium Agonists Synergistically Produce Eicosanoids Independent of Protein Synthesis in RAW264.7 Cells
Arachidonic acid is released by phospholipase A2 and converted into hundreds of distinct bioactive mediators by a variety of cyclooxygenases (COX), lipoxygenases (LO), and cytochrome P450s. Because of the size and diversity of the eicosanoid class of signaling molecules produced, a thorough and syst...
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Veröffentlicht in: | The Journal of biological chemistry 2007-08, Vol.282 (31), p.22834-22847 |
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creator | Buczynski, Matthew W. Stephens, Daren L. Bowers-Gentry, Rebecca C. Grkovich, Andrej Deems, Raymond A. Dennis, Edward A. |
description | Arachidonic acid is released by phospholipase A2 and converted into hundreds of distinct bioactive mediators by a variety of cyclooxygenases (COX), lipoxygenases (LO), and cytochrome P450s. Because of the size and diversity of the eicosanoid class of signaling molecules produced, a thorough and systematic investigation of these biological processes requires the simultaneous quantitation of a large number of eicosanoids in a single analysis. We have developed a robust liquid chromatography/tandem mass spectrometry method that can identify and quantitate over 60 different eicosanoids in a single analysis, and we applied it to agonist-stimulated RAW264.7 murine macrophages. Fifteen different eicosanoids produced through COX and 5-LO were detected either intracellularly or in the media following stimulation with 16 different agonists of Toll-like receptors (TLR), G protein-coupled receptors, and purinergic receptors. No significant differences in the COX metabolite profiles were detected using the different agonists; however, we determined that only agonists creating a sustained Ca2+ influx were capable of activating the 5-LO pathway in these cells. Synergy between Ca2+ and TLR pathways was detected and discovered to be independent of NF-κB-induced protein synthesis. This demonstrates that TLR induction of protein synthesis and priming for enhanced phospholipase A2-mediated eicosanoid production work through two distinct pathways. |
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Because of the size and diversity of the eicosanoid class of signaling molecules produced, a thorough and systematic investigation of these biological processes requires the simultaneous quantitation of a large number of eicosanoids in a single analysis. We have developed a robust liquid chromatography/tandem mass spectrometry method that can identify and quantitate over 60 different eicosanoids in a single analysis, and we applied it to agonist-stimulated RAW264.7 murine macrophages. Fifteen different eicosanoids produced through COX and 5-LO were detected either intracellularly or in the media following stimulation with 16 different agonists of Toll-like receptors (TLR), G protein-coupled receptors, and purinergic receptors. No significant differences in the COX metabolite profiles were detected using the different agonists; however, we determined that only agonists creating a sustained Ca2+ influx were capable of activating the 5-LO pathway in these cells. Synergy between Ca2+ and TLR pathways was detected and discovered to be independent of NF-κB-induced protein synthesis. This demonstrates that TLR induction of protein synthesis and priming for enhanced phospholipase A2-mediated eicosanoid production work through two distinct pathways.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M701831200</identifier><identifier>PMID: 17535806</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; Arachidonate 5-Lipoxygenase - metabolism ; Calcium - metabolism ; Cell Line ; Eicosanoids - metabolism ; Gene Expression Regulation ; Lipids - chemistry ; Mice ; Models, Biological ; NF-kappa B - metabolism ; Phospholipases A - metabolism ; Prostaglandin-Endoperoxide Synthases - metabolism ; Time Factors ; Toll-Like Receptor 4 - physiology</subject><ispartof>The Journal of biological chemistry, 2007-08, Vol.282 (31), p.22834-22847</ispartof><rights>2007 © 2007 ASBMB. 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Synergy between Ca2+ and TLR pathways was detected and discovered to be independent of NF-κB-induced protein synthesis. This demonstrates that TLR induction of protein synthesis and priming for enhanced phospholipase A2-mediated eicosanoid production work through two distinct pathways.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Arachidonate 5-Lipoxygenase - metabolism</subject><subject>Calcium - metabolism</subject><subject>Cell Line</subject><subject>Eicosanoids - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Lipids - chemistry</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>NF-kappa B - metabolism</subject><subject>Phospholipases A - metabolism</subject><subject>Prostaglandin-Endoperoxide Synthases - metabolism</subject><subject>Time Factors</subject><subject>Toll-Like Receptor 4 - physiology</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2P0zAQhi0EYsvClSPyAXFL8dhx4hyrallWKgLtLoKbFduT1qvELnECqvbP46qV9oSYw3xIzzsazUvIW2BLYHX58cHY5ZeagRLAGXtGFsCUKISEn8_JgjEORcOluiCvUnpgOcoGXpILqKWQilUL8ni_uS1K2gZH7-Y0tT6go-u2t34e6Gobg09ToneHgOM2t962fX-g38boZov0ytuY2hC9S_QmONxjTmGisTsiE_pwlE47TD7RPNyufvCqXNZ0jX2fXpMXXdsnfHOul-T7p6v79edi8_X6Zr3aFFZKMRVK1KAaaayEToAB58pGNVUnBKttY50pZeskVhVy5kByKLmxNTedkQ0oZ8Ql-XDaux_jrxnTpAefbL6gDRjnpCsF-TOK_xeEpuZKCpXB5Qm0Y0xpxE7vRz-040ED00dfdPZFP_mSBe_Om2czoHvCz0Zk4P0J2Pnt7o8fURsf7Q4HzRXXAjTnSpQZUycM879-exx1sh6DRZcldtIu-n-d8BdyCqb6</recordid><startdate>20070803</startdate><enddate>20070803</enddate><creator>Buczynski, Matthew W.</creator><creator>Stephens, Daren L.</creator><creator>Bowers-Gentry, Rebecca C.</creator><creator>Grkovich, Andrej</creator><creator>Deems, Raymond A.</creator><creator>Dennis, Edward A.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20070803</creationdate><title>TLR-4 and Sustained Calcium Agonists Synergistically Produce Eicosanoids Independent of Protein Synthesis in RAW264.7 Cells</title><author>Buczynski, Matthew W. ; 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subjects | Adenosine Triphosphate - metabolism Animals Arachidonate 5-Lipoxygenase - metabolism Calcium - metabolism Cell Line Eicosanoids - metabolism Gene Expression Regulation Lipids - chemistry Mice Models, Biological NF-kappa B - metabolism Phospholipases A - metabolism Prostaglandin-Endoperoxide Synthases - metabolism Time Factors Toll-Like Receptor 4 - physiology |
title | TLR-4 and Sustained Calcium Agonists Synergistically Produce Eicosanoids Independent of Protein Synthesis in RAW264.7 Cells |
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