Regulation of TNF‐induced oxygen radical production in human neutrophils: role of δ‐PKC

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: superoxide anion generation;    p47phox;    fMet‐;    Leu‐;    Phe;    ERK;    PI 3‐;    kinase;    phosphorylation;   

DOI  :  10.1189/jlb.0408230

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Inhumanneutrophils,TNF‐elicitedO2−productionrequiresadherenceandintegrinactivation.HowthiscooperativesignalingbetweenTNFRsandintegrinsregulatesO2−generationhasyettobefullyelucidated.Previously,weidentifiedδ‐PKCasacriticalearlyregulatorofTNFsignalinginadherentneutrophils.Inthisstudy,wedemonstratethatinhibitionofδ‐PKCwithadominant‐negativeδ‐PKCTATpeptideresultedinasignificantdelayintheonsettimeofTNF‐elicitedO2−generationbuthadnoeffectonVmax,indicatinganinvolvementofδ‐PKCintheinitiationofO2−production.Incontrast,fMLP‐elicitedO2−productioninadherentandnonadherentneutrophilswasδ‐PKC‐independent,suggestingdifferentialregulationofO2−production.AnimportantstepinactivationoftheNADPHoxidaseisphosphorylationofthecytosolicp47phoxcomponent.Inadherentneutrophils,TNFtriggeredatime‐dependentassociationofδ‐PKCwithp47phox,whichwasassociatedwithp47phoxphosphorylation,indicatingaroleforδ‐PKCinregulatingO2−productionatthelevelofp47phox.ActivationofERKandp38MAPKisalsorequiredforTNF‐elicitedO2−generation.TNF‐mediatedERKbutnotp38MAPKrecruitmenttop47phoxwasδ‐PKC‐dependent.δ‐PKCactivityiscontrolledthroughserine/threoninephosphorylation,andphosphorylationofδ‐PKC(Ser643)andδ‐PKC(Thr505)wasincreasedsignificantlybyTNFinadherentcellsviaaPI3K‐dependentprocess.Thus,signalingforTNF‐elicitedO2−generationisregulatedbyδ‐PKC.Adherence‐dependentcooperativesignalingactivatesPI3Ksignaling,δ‐PKCphosphorylation,andδ‐PKCrecruitmenttop47phox.δ‐PKCactivatesp47phoxbyserinephosphorylationorindirectlythroughcontrolofERKrecruitmenttop47phox...

【 授权许可】

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