Endogenous Epoxygenases Are Modulators of MonocyteMacrophage Activity 英文参考文献.docVIP

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Endogenous Epoxygenases Are Modulators of MonocyteMacrophage Activity 英文参考文献.doc

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Endogenous Epoxygenases Are Modulators of MonocyteMacrophage Activity 英文参考文献

EndogenousEpoxygenasesAreModulatorsofMonocyte/ MacrophageActivity JonasBystrom1.,JessicaA.Wray1.¤a,MaryC.Sugden2,MarkJ.Holness2,KarenE.Swales1¤b,TimothyD. Warner1,MatthewL.Edin3,DarrylC.Zeldin3,DerekW.Gilroy4,DavidBishop-Bailey1* 1WilliamHarveyResearchInstitute,QueenMaryUniversityLondon,London,UnitedKingdom,2BlizzardInstituteofCellandMolecularScience,BartsandtheLondon, QueenMaryUniversityLondon,London,UnitedKingdom,3DivisionofIntramuralResearch,NationalInstituteofEnvironmentalHealthSciences/NationalInstitutesof Health,ResearchTrianglePark,NorthCarolina,UnitedStatesofAmerica,4DivisionofMedicine,UniversityCollegeLondon,London,UnitedKingdom Abstract Background:Arachidonicacidismetabolizedthroughthreemajormetabolicpathways,thecyclooxygenase,lipoxygenase andCYP450enzymesystems.Unlikecyclooxygenase andlipoxygenases,theroleofCYP450epoxygenasesinmonocyte/ macrophage-mediatedresponsesisnotknown. Methodology/PrincipalFindings:Whentransfectedinvitro,CYP2J2isanefficientactivatorofanti-inflammatorypathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) a. Human monocytes and macrophages containPPARaandhereweshowtheyexpresstheepoxygenasesCYP2J2andCYP2C8.Inhibitionofconstitutivemonocyte epoxygenasesusingtheepoxygenaseinhibitorSKF525Ainducescyclooxygenase(COX)-2expressionandactivity,andthe releaseofTNFa,andcanbereversedbyeitheraddbackoftheendogenousepoxygenaseproductsandPPARaligand11,12- epoxyeicosatrienoicacid(EET)ortheadditionoftheselectivesyntheticPPARaligandGW7647.Inalternativelyactivated(IL- 4-treated) monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNFa release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNFa by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl2. Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition e