Predicting Novel Features of Toll-Like Receptor 3 Signaling in Macrophages 英文参考文献.docVIP

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Predicting Novel Features of Toll-Like Receptor 3 Signaling in Macrophages 英文参考文献.doc

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Predicting Novel Features of Toll-Like Receptor 3 Signaling in Macrophages 英文参考文献

PredictingNovelFeaturesofToll-LikeReceptor3 SignalinginMacrophages MohamedHelmy1,2,JinGohda3,Jun-ichiroInoue3,MasaruTomita1,MasaTsuchiya1* ,Kumar Selvarajoo1* 1Institute forAdvancedBiosciences,KeioUniversity, Tsuruoka,Japan, 2SystemsBiologyProgram,School ofMediaandGovernance,KeioUniversity, Fujisawa,Japan, 3DivisionofCellularandMolecularBiology,InstituteofMedicalScience,UniversityofTokyo,Tokyo,Japan Abstract TheToll-likereceptor(TLR)3playsacriticalroleinmammalianinnateimmuneresponseagainstviralattacksbyrecognizing double-strandedRNA(dsRNA)oritssyntheticanalogpolyinosinic-polycytidylicacid(poly(I:C)).Thisleadstotheactivation ofMAPkinasesandNF-kBwhichresultsintheinductionoftypeIinterferonsandproinflammatorycytokinestocombatthe viralinfection.TounderstandthecomplexinterplayofthevariousintracellularsignalingmoleculesintheregulationofNF- kBandMAPkinases,wedevelopedacomputationalTLR3modelbaseduponperturbation-responseapproach.Wecurated literatureanddatabasestodeterminetheTLR3signalingtopologyspecificallyformurinemacrophages.Forinitialmodel creation,weusedwildtypetemporalactivationprofilesofMAPkinasesandNF-kBand,formodeltesting,usedTRAF6KO and TRADD KO data. From dynamic simulations we predict i) the existence of missing intermediary steps between extracellularpoly(I:C)stimulationandintracellularTLR3binding,andii)thepresenceofanovelpathwaywhichisessential for JNK and p38, but not NF-kB, activation. Our work shows activation dynamics of signaling molecules can be used in conjunctionwithperturbation-responsemodelstodeciphernovelsignalingfeaturesofcomplicatedimmunepathways. Citation: HelmyM, GohdaJ,InoueJ-i,TomitaM,TsuchiyaM,et al.(2009)Predicting Novel Features ofToll-LikeReceptor 3SignalinginMacrophages.PLoS ONE4(3):e4661.doi:10.1371/journal.pone.0004661 Editor:DeryaUnutmaz,NewYorkUniversitySchoolofMedicine,UnitedStatesofAmerica ReceivedDecember11,2008;AcceptedJanuary26,2009;PublishedMarch2,2009 Copyright: ? 2009 Helmy et al. This is an open-access article dist