TheroleofHemophilusinfluenzaeinearinfectionsandchronicobstructivepulmonarydiseaseincludestheinductionofaninflammatoryresponsethroughactivationofthetranscriptionfactorNF-kB.InadditiontoactivationofinflammatorycytokinegeneslikeIL-1andTNF,H.influenzaeactivatesTLR2expressionandgenesinvolvedinmucusproduction.HemophilusinfluenzaeactivatesNF-kBbymultiplemechanisms,startingwithactivationoftheToll-likereceptor2(TLR2)bythep16proteinintheH.influenzaeoutermembrane.TLR2playsakeyroleininnateimmuneresponsesandisexpressedinhighlevelsinlymphoidcellsaswellaslowlevelsinepithelialcells.TheroleofTLR2wassupportedbyblockingNF-kBactivationwithadominantnegativeTLR2andincreasingitwithtransfectionofanormalTLR2gene.TLR2inturnactivatesTAK1,whichactivatestwodivergentsignalingpathways.OneofthesepathwaysleadstoIkBkinaseactivation,IkBphosphorylationanddegradation,releasingtheNF-kBheterodimertotranslocateintothenucleusandactivatetranscriptionoftargetgenes.Inthealternatepathway,TAK1alsoactivatesNF-kBthroughaMapkinasepathway,activatingp38andNF-kBinanucleartranslocationindependentmanner.InvestigationofthemechanismsofH.influenzaesignalinginvolvedinNF-kBactivationmayprovidetheinformationneededtodevelopbettertreatmentsforinflammatoryconditionscausedbythispathogen.OtherpathwaysmodulatetheroleofNF-kBinH.influenzaepathogenesis.Glucocorticoidswidelyusedasanti-inflammatorydrugsincreaseTLR2activationbyH.influenzaethroughtheNIK/I-kBkinasepathway,whiletheyrepressthep38dependentactivationofNF-kB.Therepressionofthep38pathwaybyglucocorticoidsoccursthroughactivationoftheMAPkinasephosphatase-1(MKP-1)whichdephosphorylatesanddeactivatesp38.AnotheraspectoftheinflammatoryresponsetoH.influenzaeinfectionistheproductionofexcessivemucus,contributingtotheoverallsymptomsofinfection.NF-kBactivationoftheMuc2genecontributestomucusoverproduction,inadditiontoH.influenzaeactivationoftheTGF-betareceptor,activatingSMADtranscriptionfactorsSMAD3andSMAD4.UnderstandingmechanismsthatmodifyH.influenzaesignalingwillcontributetofurtherunderstandingthepathogenesisandtreatmentofearinfectionsandchronicobstructivepulmonarydisease.

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REFERENCES:ImasatoA,etal.(2002)Inhibitionofp38MAPKbyglucocorticoidsviainductionofMAPkinasephosphatase-1enhancenontypeableHaemophilusinfluenzae-inducedexpressionoftoll-likereceptor2.J.Biol.Chem.Sep27Jono,H.etal(2002)TGF-b-SmadsignalingpathwaycooperateswithNF-kBtomediatenontypeableHaemophilusinfluenzae-inducedMUC2mucintranscription.J.Biol.Chem.Sep16Sakurai,H.etal.(1998)TGF-beta-activatedkinase1stimulatesNF-kappaBactivationbyanNF-kappaB-inducingkinase-independentmechanism.BiochemBiophysResCommun.243(2),545-9ShutoT,etal.(2002)GlucocorticoidssynergisticallyenhancenontypeableHaemophilusinfluenzae-inducedToll-likereceptor2expressionviaanegativecross-talkwithp38MAPkinase.J.Biol.Chem.277(19),17263-70ShutoT,PNAS(2001)July1798(15):8774-8779.ActivationofNF-kBbynontypeableHemophilusinfluenzaeismediatedbytoll-likereceptor2-TAK1-dependentNIK-IKKa/B-IkBaandMKK3/6-p38MAPkinasesignalingpathwaysinepithelialcells.WangB,LimDJ,HanJ,KimYS,BasbaumCB,LiJD.NovelcytoplasmicproteinsofnontypeableHaemophilusinfluenzaeup-regulatehumanMUC5ACmucintranscriptionviaapositivep38mitogen-activatedproteinkinasepathwayandanegativephosphoinositide3-kinase-Aktpathway.JBiolChem.2002Jan11;277(2):949-57.