Limited specificity of IRF3 and ISGF3 in the transcriptional innate‐immune response to double‐stranded RNA

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

关键词: pathogen response;    gene expression;    interferon;    feed‐;    forward loop;    mathematical modeling;   

DOI  :  10.1189/jlb.4A1014-483RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Theinnateimmuneresponseislargelyinitiatedbypathogen‐responsiveactivationofthetranscriptionfactorIRF3.Amongothertargetgenes,IRF3controlstheexpressionofIFN‐β,whichtriggerstheactivationofthetranscriptionfactorISGF3viatheIFNAR.IRF3andISGF3havebeenreportedtocontrolmanyofthesametargetgenesandtogether,controltheantimicrobialinnate‐immuneprogram;however,theirrespectivecontributionsandspecificitiesremainunclear.Here,weusedgenomictechnologiestocharacterizetheirspecificityintermsoftheirphysicalDNA‐bindingandgeneticfunction.WiththeuseofChiP‐seqandtranscriptomicmeasurementsinWTversusifnar−/−versusifnar−/−irf3−/−macrophagesrespondingtointracellulardsRNA,weconfirmedtheknownISGF3DNA‐bindingmotifandfurtherspecifiedadistinctIRF3consensussequence.ThefunctionalspecificityofIRF3isparticularlypronouncedincytokine/chemokineregulation;yet,eveninthecontrolofIFN‐β,thatspecificityisnotabsolute.BymathematicallymodelingIFN‐βproductionwithinanabstractedtissuelayer,wefindthatIRF3versusISGF3specificitymaybecriticaltolimitingIFN‐βproductionandISGF3activation,temporallyandspatially,butthatpartialoverlapintheirspecificityistolerableandmayenhancetheeffectivenessoftheinnate‐immuneresponse...

【 授权许可】

CC BY