IRAK4 kinase activity is not required for induction of endotoxin tolerance but contributes to TLR2‐mediated tolerance

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

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

DOI  :  10.1189/jlb.0812401

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

PriorexposuretoLPSinduces“endotoxintolerance”thatreprogramsTLR4responsestosubsequentLPSchallengebyalteringexpressionofinflammatorymediators.Endotoxintoleranceisthoughttolimittheexcessivecytokinestormandpreventtissuedamageduringsepsisbutrendersthehostimmunocompromisedandsusceptibletosecondaryinfections.ToleranceinitiatedviaoneTLRcanaffectcellularresponsestochallengeviathesameTLR(“homotolerance”)orthroughdifferentTLRs(“heterotolerance”).IRAK4,anessentialcomponentoftheMyD88‐dependentpathway,functionsasakinaseandanadapter,activatingsubsetsofdivergentsignalingpathways.Inthisstudy,weaddressedmechanisticallytheroleofIRAK4kinaseactivityinTLR4‐andTLR2‐inducedtoleranceusingmacrophagesfromWTversusIRAK4KDKImice.WhereasIRAK4kinasedeficiencydecreasedLPSsignaling,itdidnotpreventendotoxintolerance,asendotoxinpretreatmentofWTandIRAK4KDKImacrophagesinhibitedLPS‐inducedMAPKphosphorylation,degradationofIκB‐αandrecruitmentofp65totheTNF‐αpromoter,expressionofproinflammatorycytokines,andincreasedlevelsofA20andIRAK‐M.PretreatmentofWTmacrophageswithPam3Cys,aTLR2–TLR1agonist,ablatedp‐p38andp‐JNKinresponsetochallengewithPam3CysandLPS,whereasIRAK4KDKImacrophagesexhibitedattenuatedTLR2‐elicitedhomo‐andheterotoleranceatthelevelofMAPKactivation.Thus,IRAK4kinaseactivityisnotrequiredfortheinductionofendotoxintolerancebutcontributessignificantlytoTLR2‐elicitedhomo‐andheterotolerance...

【 授权许可】

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