MEK‐independent ERK activation in human neutrophils and its impact on functional responses

[摘要] Neutrophilsinfluenceinnateandadaptativeimmunity,notablythroughthegenerationofnumerouscytokinesandchemokinesandthroughthemodulationoftheirconstitutiveapoptosis.Severalsignalingcascadesareknowntocontrolneutrophilresponses,includingtheMEKpathway,whichisnormallycoupledtoERK.However,weshowherethatinhumanneutrophilsstimulatedwithcytokinesorTLRligands,MEKandERKareactivatedindependentlyofeachother.PharmacologicalblockadeofMEKhadnoeffectontheinductionofERKkinaseactivityandviceversa.InautologousPBMCexposedtothesamestimuliorinneutrophilsexposedtochemoattractants,thisuncouplingofMEKandERKwasnotobserved.WhereaswehadshownbeforethatMEKinhibitionimpairscytokinegenerationtranslationallyinLPS‐orTNF‐stimulatedneutrophils,ERKinhibitionaffectedthisresponsetranscriptionallyandtranslationally.TranscriptionaltargetsorERKincludethemitogen‐andstress‐activatedproteinkinase1(MSK‐1)anditssubstrates,C/EBPβandCREB,whereastranslationaltargetsincludetheS6kinaseanditssubstrate,theS6ribosomalprotein.Inadditiontoaffectingcytokineproduction,ERKinhibitioninterferedwithhowLPSorTNFpromotesneutrophilsurvivalandlevelsofthemyeloidcellleukemia1(Mcl‐1)antiapoptoticprotein.WhereastheERK‐activatingkinasewasnotidentified,wefoundthattheMAP3K,TGF‐β‐activatedkinase1(TAK1),actsupstreamofERKandMEKinneutrophils.OurresultsdocumentafunctionaluncouplingoftheMEK/ERKmoduleundercertainstimulatoryconditionsandsuggestthattherapeuticstrategiesbasedonMEKinhibitionmightbenefitfrombeingcomplementedbyERKinhibition,particularlyinchronicinflammatoryconditionsfeaturingastrongneutrophiliccomponent...

[学科分类] 生理学

[关键词] signaling;transcription;translation;cytokines;apoptosis