Effects of the TLR2 Agonists MALP-2 and Pam3Cys in Isolated Mouse Lungs 英文参考文献.docVIP

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Effects of the TLR2 Agonists MALP-2 and Pam3Cys in Isolated Mouse Lungs 英文参考文献.doc

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Effects of the TLR2 Agonists MALP-2 and Pam3Cys in Isolated Mouse Lungs 英文参考文献

EffectsoftheTLR2AgonistsMALP-2andPam3Cysin IsolatedMouseLungs MartinaBarrenschee,DennisLex,StefanUhlig* InstituteofPharmacologyandToxicology,UniversityHospitalAachen,RWTHAachenUniversity,Aachen,Germany Abstract Background: Gram-positive and Gram-negative bacteria are main causes of pneumonia or acute lung injury. They are recognizedbytheinnateimmunesystemviatoll-likereceptor-2(TLR2)orTLR4,respectively.Amongallorgans,thelungs havethehighestexpressionofTLR2receptors,butlittleisknownaboutthepulmonaryconsequencesoftheiractivation. Here we studied the effects of the TLR2/6 agonist MALP-2, the TLR2/1 agonist Pam3Cys and the TLR4 agonist lipopolysaccharide(LPS)onpro-inflammatoryresponsesinisolatedlungs. Methodology/PrincipalFindings:Isolatedperfusedmouselungswereperfusedfor60minor180minwithMALP-2(25ng/ mL),Pam3Cys(160ng/mL)orLPS(1mg/mL).Westudiedmediatorreleasebyenzymelinkedimmunosorbentassay(ELISA), the activation of mitogen activated protein kinase (MAPK) and AKT/protein kinase B by immunoblotting, and gene inductionbyquantitativepolymerasechainreaction.AllagonistsactivatedtheMAPKERK1/2andp38,butneitherJNKor AKT kinase. The TLR ligands upregulated the inflammation related genes Tnf, Il1b, Il6, Il10, Il12, Ifng, Cxcl2 (MIP-2a ) and Ptgs2. MALP-2 was more potent than Pam3Cys in inducing Slpi, Cxcl10 (IP10) and Parg. Remarkable was the strong inductionofTncbyMALP2,whichwasnotseenwithPam3CysorLPS.ThegrowthfactorrelatedgenesAregandHbegfwere not affected. In addition, all three TLR agonists stimulated the release of IL-6, TNF, CXCL2 and CXCL10 protein from the lungs. Conclusions/Significance:TLR2andTLR4activationleadstosimilarreactionsinthelungsregardingMAPKactivation,gene inductionandmediatorrelease.SeveralgenesstudiedherehavenotyetbeenappreciatedastargetsofTLR2-activationin thelungsbefore,i.e.,Slpi,tenascinC,PargandTraf1.Inaddition,theMALP-2dependentinductionofTncmayindicatethe existenceofTLR2/6-specificpathways. Citation:BarrenscheeM,LexD,UhligS(2010)EffectsoftheTLR2Agoni