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1、BiochimicaetBiophysicaActa1592(2002)265–280www.bba-direct.comReviewSummaryandcomparisonofthesignalingmechanismsoftheToll/interleukin-1receptorfamilyMichaelU.Martina,*,HolgerWeschebaInstituteofPharmacologyOE5320,HannoverMedicalSchool,D-30623Hanover,GermanybTula
2、rikInc.,2CorporateDrive,SouthSanFrancisco,CA94080,USAReceived27September2001;receivedinrevisedform24May2002;accepted24May2002AbstractTheToll/interleukin-1(IL-1)receptor(TIR)familycomprisestwogroupsoftransmembraneproteins,whichsharefunctionalandstructuralproper
3、ties.ThemembersoftheIL-1receptor(IL-1R)subfamilyarecharacterizedbythreeextracellularimmunoglobulin(Ig)-likedomains.Theyformheterodimericsignalingreceptorcomplexesconsistingofreceptorandaccessoryproteins.ThemembersoftheToll-likereceptor(TLR)subfamilyrecognizeal
4、armsignalsthatcanbederivedeitherfrompathogensorthehostitself.TLRspossessleucine-richrepeatsintheirextracellularpart.TLRscanformdimericreceptorcomplexesconsistingoftwodifferentTLRsorhomodimersinthecaseofTLR4.TheTLR4receptorcomplexrequiressupportivemoleculesforo
5、ptimalresponsetoitsligandlipopolysaccharide(LPS).AhallmarkoftheTIRfamilyisthecytoplasmicTIRdomainthatisindispensableforsignaltransduction.TheTIRdomainservesasascaffoldforaseriesofprotein–proteininteractionswhichresultintheactivationofauniquesignalingmodulecons
6、istingofMyD88,interleukin-1receptorassociatedkinase(IRAK)familymembersandTollip,whichisusedexclusivelybyTIRfamilymembers.Subsequently,severalcentralsignalingpathwaysareactivatedinparallel,theactivationofNFnBbeingthemostprominenteventoftheinflammatoryresponse.R
7、ecentdevelopmentsindicatethatinadditiontothecommonsignalingmoduleMyD88/IRAK/Tollip,othermoleculescanmodulatesignalingbyTLRs,especiallyofTLR4,resultingindifferentialbiologicalanswerstodistinctpathogenicstructures.SubtledifferencesinTLRsignalingpathwaysarenowbec
8、omingapparent,whichrevealhowtheinnateimmunesystemdecidesataveryearlystagethedirectioninwhichtheadaptiveimmuneresponsewilldevelop.Thecreationofpathogen-specificmediatorenvironmentsb
