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(,100101)R392111A10002484X(2005)0220083206,,19661988,1996RutgersWaksmanRobertWoodJohnsonMed2icalSchool,(1993)Dr.PhillipA.Sharp2000DupontPharmaceuticalCompany2000,,,,1957,IsaacsLindenmann1,,(IFN),,IFN2;,,IFN2,,IFN2,AIDS224,IFN2(MHV2A59,30430640);(30025010,20012004),100094,90095217815,,1Toll(TLRs)(innateim2munity)(adaptiveimmunity),,,(Pathogen2AssociatedMolecularPatterns,PAMPs)6,Toll(TollLikeReceptors,TLRs)PAMPs7,13TLRs,10,128TLRPAMPsTLR3TLR4RNA(LPS),TLR5,TLR9DNATLR7TLR8RNATLRs,TLR12346799,10,(DC)TLRs,11TLRs,TLRsNF2BMAPKsERKJNK12PAMPs,TLRs88(MyD88)P(IRAK)TNF6(TRAF6)TGF(TAK21)IKK,NF2B,NF2B,IL21,IL26TNF2(1),TAK21382MKK3MKK6,p38JNK7,12MyD88,TLRMyD88,TLR3TLR4MyD88,13,14Toll(TIR)TRIF(TIRdomain2containingadaptorinducingIFN2)TRIF,TLR3TLR4IFN215,16TLR7TLR8RNA,IFN217,18,TLR9DNA19,20TLR7TLR9MyD88,21,222I211TLR3PKRRIG21,TLRTLR3RNApolyIC23TLR3,24RNA,,RNARNA(dsRNABindingProteins,DRBPs)RNA(dsRNABindingDomains,DRBDs)11bpRNA,RNA2520DRBPs,RNA(dsRNA2dependentProteinKinase,PKR)(AdenosineDeaminaseActingonRNA,ADAR)IPKRPKRP,NDRBDsRNA,PKR,eIF22,26,27RNARIG21(RetinoicAcidInducibleGene1)RIG21DexDPHboxRNA(helicase),RNAIRF23NF2B28212IRF3IRF7IFN2IRF3(interferonregulatoryfactor23),IRF3C229,TBK1IKKiPIKKIRF330,31IRF3TBK1IKKi,CBPPP300,,IFN232234NF2Bp65IFN235TBK1,IFN2IFN2IP210RANTES36,TBK1IRF3,NF2BTBK1IKKi,,IKKiTBK1,IKKi37TBK1IK2Ki,IRFIRF7IFN2IRF3,IRF7IFN,IRF738(IFNAR),IRF7,IFN2IFN2,39,40DC,TLRIFN2,MyD88,TRAF6IRF7TRAF641DC,TLR3TLRs,dsRNApolyICIFN2,TLRs42IRF7IFN2,(plasmatoidDCcells,pDC),IRF7(constitutive),IFN23311TLR4,LPSTLR4,IRF23I(TNF2,IL21,IL26)4820052143,44LPS,IP10RANTES,IFN2IFNAR145,IF2NAR1,,LPS46,47312TLR(Listeriamono2cytogenes),,,IFN248,49,listeriolysinO(LLO)IFN250,IRF3IFNAR1,,,TLRMyD88TRIFTRAM,,IFN2,ITLR51313,DNA,LPS,52,53,49,(Burkholderiapseudomal2lei)IFN2,1(IRF21)iNOS()54IFN2P,IFN2P,AAFISGF3(1),554I411IFNP,,IFNAR,Jak2STATIFNPIFNARJak,STAT1STAT2STAT1AAF(IFN22activitedfacter);STAT1STAT2IRF92ISGF3(IFN2stimulatedgenefac2tor3)AAFISGF3,GAS(IFN22activatedsequence)ISRE(IFN2stimulatedre2sponseelement)DNA,,56258IRF7IFN2P,412,59,PKR,ADAR,OAS(2,52oligoadenylatesynthetase),RNaseLMxPKRADARRNAOASRNA,60OAS,225A(52triphosphorylated,2,52phosphodiester2linkedoligoadenylates)225ARNaseL,RNaseLRNA61,(RSV)M2RNARNaseL62MxGTPase,GT2PasedynaminMx,,MxATHOV(Thogotovirus),63,64,NKT,NKJak2STAT,NK(cyto2toxicity),65,66NK(IFN2,TNF2,GM2CSF),CD8+T(eradication)CD8+T(antigenpre2sentationcell,APC)MHC2(epitope),T(cytotoxicityTlymphocyte,CTL),MHC2,CD8+TCTL582413,,TRAIL,PKRDaxx67,,49,68,BALBPcC57BLP667,69,67,68,70,1TLRFig11TheSandglassmodelofTLRsignalinginregulationofgeneexpressionoftypeIinterferonsandinflammatorycytokinesNote:ThousandsofpathogenicPAMPscanberecognizedbyadozenofTLRsandtransmittedtotheir4downstreamadaptorfactors(MyD88,TRAM,TIRAPandTRIF).Twoessentialkinased(TBK1andIKKiP)thenrelaythesignalstoactivateanoceanofanti2viralcytokines(e.g.,IRF3P7dependenttypeIinter2ferons)andinflammatorycytokines(e.g.,NF2BdependentIL21,TNF).Questionmarksstandforthepathwaystobeelucidated.5TLR,,,,,NS1PKR,IFN2P71,72,(non2re2sponder)73,74,,IFN275,6820052161IsaacsA,LindenmannJ.VirusinterferenceI.TheinterferonJ.ProcRSocLondBBiolSci,1957;147(927):2582267.2CooksleyWG.Treatmentwithinterferons(includingpegylatedinterfer2ons)inpatientswithhepatitisBJ.SeminLiverDis,2004;24(1):45253.3PawlotskyJM.Thenatureofinterferon2alpharesistanceinhepatitisCvir2usinfectionJ.CurrOpinInfectDis,2003;16(6):5872592.4BayasA,GoldR.Lessonsfrom10yearsofinterferonbeta21b(BetaferonPBetaseron)treatmentJ.JNeurol,2003;250(4):328.5ParmarS,PlataniasLC.Interferons:mechanismsofactionandclinicalapplicationsJ.CurrOpinOncol,2003;15(6):4312439.6JanewayCA,JrMedzhitovR.InnateimmunerecognitionJ.AnnuRevImmunol,2002;20:1972216.7VaidyaSA,ChengG.Toll2likereceptorsandinnateantiviralresponsesJ.CurrOpinImmunol,2003;15(4):4022407.8BeutlerB.Inferences,questionsandpossibilitiesinToll2likereceptorsig2nallingJ.Nature,2004;430(6996):2572263.9TakeuchiO,SatoS,HoriuchiTetal.Cuttingedge:roleofToll2likere2ceptor1inmediatingimmuneresponsetomicrobiallipoproteinsJ.JImmunol,2002;169(1):10214.10MuzioM,BosisioD,PolentaruttiNetal.Differentialexpressionandregulationoftoll2likereceptors(TLR)inhumanleukocytes:selectiveexpressionofTLR3indendriticcellsJ.JImmunol,2000;164(11):599826004.11ReisE,SousaC.Toll2likereceptorsanddendriticcells:forwhomthebugtollsJ.SeminImmunol,2004;16(1):27234.12BartonGM,MedzhitovR.Toll2likereceptorsignalingpathwaysJ.Sci2ence,2003;300(5625):152421525.13AkiraS,HoshinoK,KaishoT.TheroleofToll2likereceptorsandMyD88ininnateimmuneresponsesJ.JEndotoxinRes,2000;6(5):3832387.14YamamotoM,SatoS,MoriKetal.Cuttingedge:anovelTollPIL21re2ceptordomain2containingadapterthatpreferentiallyactivatestheIFN2be2tapromoterintheToll2likereceptorsignalingJ.JImmunol,2002;169(12):666826672.15HoebeK,DuX,GeorgelPetal.IdentificationofLps2asakeytrans2ducerofMyD882independentTIRsignallingJ.Nature,2003;424(6950):7432748.16YamamotoM,SatoS,HemmiHetal.RoleofadaptorTRIFintheMyD882independenttoll2likereceptorsignalingpathwayJ.Science,2003;301(5633):6402643.17DieboldSS,KaishoT,He