Abrogation of NF‐κB signaling in human neutrophils induces neutrophil survival through sustained p38‐MAPK activation

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

关键词: chronic inflammation;    COPD;    diseases;    apoptosis;   

DOI  :  10.1189/jlb.0809544

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

NF‐κB,animportanttranscriptionfactorintheregulationofcellularinflammation,isoneoftheprimetargetsfornovelanti‐inflammatorytherapeutics.Nowadays,anti‐inflammatorytherapiesrelymostlyonsteroids,whichamongothereffects,inhibitNF‐κBactivity.However,steroidshaveonlylimitedefficacyinthetreatmentonneutrophil‐drivendiseases,suchasCOPD.HumanneutrophilsplayanimportantroleinthepathogenesisofCOPD,andclearanceofthesecellsbyapoptosisisaneffectivepathwayforresolutionofinflammation.Inthisstudy,wetestedthehypothesisthatmodulationoftheNF‐κBpathwayinhumanneutrophilsaffectssurvival.Importantly,thepharmacologicalNF‐κBinhibitorBay11‐7082inhibitedNF‐κBsignalinginhumanneutrophilsasexpected.However,wefoundthatcompleteinhibitionofNF‐κBactivitywith10μMBay11‐7082prolongedneutrophilsurvivalsignificantly,whichwasnotobservedwithinhibitorsforothersignalingpathways.Bay11‐7082‐inducedneutrophilsurvivalwasdependentonp38‐MAPKkinaseactivity,asthep38kinaseactivityinhibitorSB203580abrogatedthisresponsecompletely.Bay11‐7082inducedrapidandsustainedp38activationthatcorrelatedwithinhibitedNF‐κBsignalingandprolongedneutrophilsurvival.ThepreciseroleofNF‐κBinregulationofp38‐MAPKactivationremainstobeestablished.Undertheseconditionsofsurvival,thestabilityofBcl‐xLbutnotMcl‐1wasenhanced.AlthoughinhibitionofNF‐κBleadstodown‐regulationofinflammatorygenesinmanycelltypes,ourresultsillustratethatinterferencewithbasalNF‐κBsignalinginneutrophilsasadrugtargetshouldbeusedwithcaution...

【 授权许可】

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