Toll样受体信号通路中MyD88的研究进展_吴燕燕

20123283IMMUNOLOGICALJOURNALVol.28No.3Mar.2012Toll（Toll-likereceptors，TLRs）（pathogenassociatedmolecularpattern,PAMP），[1]。MyD88（myeloiddifferentiationfactor88），，296，2，N（deathdomain,DD）CTIR（Toll/IL-1Rdomain,TIR）。，MyD88，。1MyD88MyD88CTIRTIR，。MyD88Toll/IL-1，：IL-1R、IL-18RTLRs。1.1IL-1IL-1IIL-1、IL-1RAcP、IL-1Rrp、IL-1RAcPLT1/ST2。LiMyD88IL-1RAcPTIR。Myc-IL-1RAcPAU1-MyD88HEK293T。Westernblot，：MyD88D195A/R196A/D197AIL-1RAcP。，MyD88IL-1RAcP，MyD88IL-1RAcP[2]。ST2，IL-1，。IL-1LPSNF-κB。ST2IL-1、LPSCpG，TLR3Poly(I:C)NF-κB。ST2MyD88MAL（MyD88-adapter-like，TIRAP），TRIF（TIRdomaincontainingadaptorinducinginterferonβ，TICAM-1）IRAK（IL-1receptor-associatedkinase）。ST2MyD88MAL[3-4]。1.2Toll/TLRTLRs，TLR5、TLR7、TLR8TLR9MyD88；TLR1/2、TLR2/6TLR4MALMyD88，[5-7]。TLR4MyD88TRIF2。MyD88，TLR4MyD88[]1000-8861（2012）03-0262-04TollMyD88，*··[]MyD88Toll，。MyD88，。[]MyD88；Toll；[]R392.12[]ATheprogressintheMyD88-dependentreceptorsignalingpathwayWUYanyan,WANGYiDepartmentofImmunologyandPathogenBiology,ShanghaiUniversityofTraditionalChineseMedicine,Shanghai201203,China[Abstract]Toll-likereceptors(TLRs)areimportanttoinitiatetheinnateimmuneresponsetoawidevarietyofpathogens.RecentstudieshaverevealedtheimportanceoftheTLRsinpathogenrecognitionandsignaling.MyD88isanessentialadaptorproteinthatintegratesandtransducesintracellularsignalinggeneratedbyTLRs.Here,wesummarizerecentadvancesintheMyD88-dependentreceptorsignalingpathway.[Keywords]MyD88；Toll-likereceptors；Cytokines：（，J50301）：201203，*：，E-mail：[e-mail]262··DOI:10.13431/j.cnki.immunol.j.2012005920123283IMMUNOLOGICALJOURNALVol.28No.3Mar.2012MAL。Horng：TLR5、TLR7TLR9TIRAP（MAL），。，，NF-κBMAPK[5-6]。（adeno-associatedviruses,AAVs），，AAVs。，。AAVsI。、MyD88、TRIFTLR-9C57BL/6（plasmacytoidDCs,pDCs）。AAV2-lacZ，，ELISAIFN-αIFN-β。：TRIFIFN-αINF-β，MyD88TLR-9IFN-αIFN-β。，AAV2MyD88TLR-9[8]。2MyD88MyD88，。MyD88TLRs，IRAK。IRAK-1Tollip（Toll-interactingprotein）。，IRAK-4IRAK-1，TollipMyD88。，MyD88CTIR，NDDIRAK-1、IRAK-4TRAF6（TNFR-associatedfactor6）。IRAK-1TRAF-6，MyD88。TRAF-6Ubc13/UevlATRAF663。TRAF6TAB-1（TAK-1bindingprotein-1）TAB-2（TAK-1bindingprotein-2），MAP3KTAK1（TGF-β-activatedkinase-1）TAK-1。TAK-1MAPK（mitogen-activatedproteinkinases）IKK（IκBkinase），2。，NF-κBI-κB（inhibitor-κB），NF-κB，NF-κBI-κB。IKKIKKαIKKβIKKγ（NEMOIKKAP），I-κB，NF-κB，NF-κBNF-κB，。TAK-1MAPK，ERK、JUKp38，c-Junc-fos，c-Junc-fos，AP-1，IL-1、IL-6TNF-α[7,9-16]（1[17]）。，pDC（plasmacytoidDCs），TLR7/MyD88TLR9/MyD881TLRsFig1TLRssignalingpathway263··20123283IMMUNOLOGICALJOURNALVol.28No.3Mar.2012，I，IFN-α、IFN-β。MyD88NF-κBIRF-7，I[18-20]。，STAP-2MyD88IKK，IRAK1TRAF6NF-κB[21]。。MyD88。MyD88sMyD88，DDTIR，，IRAK4，NF-κB[22]。IRAK-MIRAK，/，MyD88IRAK-4、IRAK-1MyD88。IRAK-M-/-，[23]。Nrdp1E3，MyD88，[24]。3MyD88IL-6，，。，MyD88IL-6。LoiarroMyD88TIRBB-loopST2825。ST2825MyD88，IRAK1IRAK4，MyD88。2、3，20μg/kgIL-1β。5min（50mg/kg、100mg/kg200mg/kg）ST2825，ELISA100mg/kg200mg/kgIL-6（P0.01）[25]。，（Heat-killedBrucellaabortus,HKBA）Th1。，C57BL/6HKBA，TNF2h；MyD88HKBA，1h、2h3hTNF。，HKBATNFMyD88[26]。KaishoLPSMyD88CD4+T。，LPS，CD4+TIFN-γIL-12，IL-4。，MyD88CD4+TIFN-γIL-12，IL-4[27]。IL-23IL-12，Th17。IL-23，IL-23。LiuIL-23p19TLR-4/MyD88。3MAPK（ERK、JNKp38）p19。1.3kbp19，RACE。IL-23p19，（-413+10）NF-κBAP-1。NF-κB，AP-1p19，AP-1p19。（EMSA），c-Junc-FosAP-1。c-JunATF-2p19。，TLR/MyD88MAPKNF-κBIL-23p19[28]。4MyD88，，。MyD88，MyD88。MyD88，。【】[1],,.Toll[J].,2011,27(2):165-169.[2]LiC,ZienkiewiczJ,HawigerJ,etal.InteractivesitesintheMyD88Toll/interleukin(IL)1receptordomainresponsibleforcouplingtotheIL1betasignalingpathway[J].JBiolChem,2005,280(28):26152-26159.[3]BrintEK,XuD,LiuH,etal.ST2isaninhibitorofinterleukin1receptorandToll-likereceptor4signalingandmaintainsendotoxintolerance[J].NatureImmunol,2004,5(4):373-379.[4]BrintEK,FitzqeraldKA,SmithP,etal.Characterizationofsignalingpathwaysactivatedbytheinterleukin1(IL-1)receptorhomologueT1/ST2.AroleforJunN-terminalkinaseinIL-4induction[J].JBiloChem,2002,277(51):49205-49211.[5]HorngT,BartonGM,FlavellRA,etal.TheadaptormoleculeTIRAPprovidessignalingspecificityforToll-likereceptors[J].Nature,2002,420(6913):329-333.[6]YamamotoM,SatoS,HemmiH,etal.EssentialroleforTIRAPinactivationofthesignalingcascadesharedbyTLR2andTLR4[J].Nature,2002,420(6913):324-329.[7]KaishoT,AkiraS.Toll-likereceptorfunctionandsignaling[J].JAllergyClinImmunol,2006,117(5):979-987.264··20123283IMMUNOLOGICALJOURNALVol.28No.3Mar.2012[8]ZhuJ,HuangX,YangY.TheTLR9-MyD88pathwayiscriticalforadaptiveimmuneresponsestoadeno-associatedvirusgenetherapyvectorsinmice[J].JClinInvest,2009,119(8):2388-2398.[9]LiX,QinJ.ModulationofToll-interleukin1receptormediatedsignaling[J].JMolMed,2005,83(4):258-266.[10]SuzukiN,SuzukiS,DuncanGS,etal.Severeimpairmentofinterleukin-1andToll-likereceptorsignalinginmicelackingIRAK-4[J].Nature,2002,416(6882):750-756.[11]MotshwenePG,MoncrieffeMC,GrossmannJG,etal.Anoligomericsignalingplatformformedbythetoll-likereceptorsignaltransducersMyD88andIRAK4[J].JBiolChem,2009,284(37):25404-25411.[12]KonnoH,YamamotoT,YamazakiK,etal.TRAF6establishesinnateimmuneresponsesbyactivatingNF-kappaBandIRF7uponsensingcytosolicviralRNAandDNA[J].PLoSOne,2009,4(5):e5674.[13]SatoS,SanjoH,TakedaK,etal.Essentialfunctionofthek