MAP kinase p38α regulates type III interferon (IFN‐λ1) gene expression in human monocyte‐derived dendritic cells in response to RNA stimulation

[摘要] RecognitionofviralnucleicacidsleadstotypeIandtypeIIIIFNgeneexpressionandactivationofhostantiviralresponses.Atpresent,typeIIIIFNgenesaretheleastwell‐characterizedIFNtypes.Here,wedemonstratethatthep38MAPKsignalingpathwayisinvolvedinregulatingIFN‐λ1geneexpressioninresponsetovarioustypesofRNAmoleculesinhumanmoDCs.Inhibitionofp38MAPKstronglyreducedIFNgeneexpression,andoverexpressionofp38αMAPKenhancedIFN‐λ1geneexpressioninRNA‐stimulatedmoDCs.TheregulationofIFNgeneexpressionbyp38MAPKsignalingwasindependentofproteinsynthesisandthus,adirectresultofRNAstimulation.Moreover,theRIG‐I/MDA5‐MAVS‐IRF3pathwaywasrequiredforp38αMAPKtoup‐regulateIFN‐λ1promoteractivation,whereastheMyD88‐IRF7pathwaywasnotneeded,andtheregulationwasnotinvolveddirectlyinIRF7‐dependentIFN‐α1geneexpression.Thestimulatoryeffectofp38αMAPKonIFN‐λ1mRNAexpressioninhumanmoDCsdidnottakeplacedirectlyviatheactivatingTBK1/IKKɛcomplex,butrather,itoccurredthroughsomeotherparallelpathways.Furthermore,mutationsinISREandNF‐κBbindingsitesinthepromoterregionoftheIFN‐λ1geneledtoasignificantreductioninp38αMAPK‐mediatedIFNresponsesafterRNAstimulation.Altogether,ourdatasuggestthatthep38αMAPKpathwayislinkedwithRLRsignalingpathwaysandregulatestheexpressionofearlyIFNgenesafterRNAstimulationcooperativelywithIRF3andNF‐κBtoinduceantiviralresponsesfurther...

[学科分类] 生理学

[关键词] RIG‐I‐like receptors;signaling;transcription;IRF3;NF‐κB