Pellino‐3 promotes endotoxin tolerance and acts as a negative regulator of TLR2 and TLR4 signaling

[摘要] DevelopmentofendotoxintoleranceinmacrophagesduringsepsisreprogramsToll‐likereceptor4signalingtoinhibitproinflammatorycytokineswithoutsuppressinganti‐inflammatoryandantimicrobialmediatorsandprotectsthehostfromexcessiveinflammationandtissuedamage.However,endotoxintolerancerenderssepticpatientsimmunocompromisedandunabletocontrolsecondaryinfections.AlthoughpreviousstudieshaverevealedtheimportanceofseveralnegativeregulatorsofToll‐likereceptorsignalinginendotoxintolerance,theroleofPellinoproteinshasnotbeenaddressed.ThepresentreportshowsthattheinductionofendotoxintoleranceinvivoinmiceandinvitroinhumanmonocytesandTHP‐1andMonoMac‐6macrophagesincreasestheexpressionofPellino‐3.OverexpressionofPellino‐3inhumanembryonickidney293/Toll‐likereceptor2or293/Toll‐likereceptor4/myeloiddifferentiationfactor‐2cellsinhibitedToll‐likereceptor2/4‐mediatedactivationofnuclearfactor‐κBandinductionofCXCL‐8mRNA,andPellino‐3ablationincreasedtheseresponses.Pellino‐3‐deficientTHP‐1cellshadelevatedToll‐likereceptor2/4‐driventumornecrosisfactor‐α,interleukin‐6mRNA,andToll‐likereceptor4‐drivenCCL5geneexpressioninresponsetoToll‐likereceptoragonistsandheat‐killedEscherichiacoliandStaphylococcusaureus,cytokinescontrolledbytheMyD88andToll‐interleukin‐1Rdomain‐containingproteininducinginterferon‐β‐mediatedpathways,respectively.Inaddition,deficiencyinPellino‐3slightlyincreasedphagocytosisofheat‐killedbacteria.TransfectedPellino‐3inhibitednuclearfactor‐κBactivationdrivenbyoverexpressionofMyD88,TIRdomain‐containingadapterinducinginterferon‐β,interleukin‐1R‐associatedkinase‐1,andtumornecrosisfactorreceptoractivatorofnuclearfactor‐κB‐bindingkinase‐1,TGF‐β‐activatedkinase1,andtumornecrosisfactorreceptor‐associatedfactor‐6,andinhibitedinterleukin‐1R‐associatedkinase1modificationsandtumornecrosisfactorreceptoractivatorofnuclearfactor‐κB‐bindingkinase1phosphorylation.Finally,Pellino‐3ablationinTHP‐1decreasedtheextentofendotoxintolerization.Thus,Pellino‐3isinvolvedinendotoxintoleranceandfunctionsasanegativeregulatorofToll‐likereceptor2/4signaling...

[学科分类] 生理学

[关键词] Toll‐like receptors;signal transduction;innate immunity;inflammation;lipopolysaccharide