Reduced transcript stabilization restricts TNF‐α expression in RAW264.7 macrophages infected with pathogenic mycobacteria: evidence for an involvement of lipomannan

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: monocyte;    paratuberculosis;    lipopolysaccharide;    lipoglycan;    p38 mitogen‐;    activated protein kinase;    post‐;    transcriptional gene regulation;   

DOI  :  10.1189/jlb.0309207

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

DespitethecriticalrolethatTNF‐αplaysinthecontainmentofmycobacterialinfection,themechanismsinvolvedinregulationofitsexpressionbymycobacteriaarepoorlydefined.WeaddressedthisquestionbystudyingMAP,whichcausesachronicenteritisinruminantsandislinkedtohumanCrohn'sdisease.WefoundthatinMAP‐infectedmacrophages,TNF‐αgeneexpressionwassubstantiallylowerthaninmacrophagesinfectedwithnonpathogenicMSorstimulatedwithLPS.TNF‐αtranscriptionalonecouldnotfullyexplainthedifferentialTNF‐αmRNAexpression,suggestingthattheremustbeasubstantialcontributionbypost‐transcriptionalmechanisms.Accordingly,wefoundreducedTNF‐αmRNAstabilityinMAP‐infectedmacrophages.FurthercomparisonofMAP‐andMS‐infectedmacrophagesrevealedthatlowerTNF‐αmRNAstabilitycombinedwithlowermRNAandproteinexpressioninMAP‐infectedmacrophagescorrelatedwithlowerp38MAPKphosphorylation.ThesesfindingswereindependentofviabilityofMAPandMS.Wedemonstratethatthemajormycobacterialcell‐walllipoglycanLMofMAPandMSinducedTNF‐αmRNAtranscription,butonlytheMS‐LMinducedp38MAPK‐dependenttranscriptstabilization.Overall,ourdatasuggestthatpathogenicmycobacteriacauseweakp38MAPKactivationandTNF‐αmRNAstabilizationasaresultoftheirstructuralcell‐wallcomponentssuchasLMandthereby,restrictTNF‐αexpressioninmacrophages...

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