Induction of endotoxin tolerance in vivo inhibits activation of IRAK4 and increases negative regulators IRAK‐M, SHIP‐1, and A20

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

关键词: lipopolysaccharide;    signal transduction;    tolerance/suppression/anergy;    cell activation;    monocytes/macrophages;   

DOI  :  10.1189/jlb.0611273

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

TLRsmediatehostdefenseagainstmicrobialpathogensbyelicitingproductionofinflammatorymediatorsandactivatingexpressionofMHC,adhesion,andcostimulatorymolecules.EndotoxintolerancelimitsexcessiveTLR‐driveninflammationduringsepsisandreprogramsmacrophageresponsestoLPS,decreasingexpressionofproinflammatorycytokineswithoutinhibitinganti‐inflammatoryandantimicrobialmediators.MolecularmechanismsofreprogrammingofTLR4signalinguponinvivoinductionofendotoxintoleranceareincompletelyunderstood.Weusedaninvivomodelofendotoxintolerance,wherebyC57BL/6micewerei.p.‐inoculatedwithLPSorPBS,followedbyinvitrochallengeofperitonealorsplenicmacrophageswithLPStoexamineactivationofIRAK4andexpressionofnegativeregulatorymolecules.AdministrationofLPSinvivo‐inducedendotoxintoleranceinperitonealandsplenicmacrophages,asevidencedbydecreaseddegradationofIκBα,suppressedphosphorylationofp38andreducedexpressionofTNF‐α,IL‐6,andKCmRNAuponinvitroLPSchallenge.Macrophagesfromcontrolandendotoxin‐tolerantmiceexhibitedcomparableTLR4mRNAlevelsandsimilarexpressionofIL‐1RAandIL‐10genes.EndotoxintolerizationinvivoblockedTLR4‐drivenIRAK4phosphorylationandactivationinmacrophages,whileincreasingexpressionofIRAK‐M,SHIP‐1,A20mRNA,andA20protein.Thus,inductionofendotoxintoleranceinvivoinhibitsexpressionofproinflammatorymediatorsviaimpairedactivationofIRAK4,p38,andNF‐κBandincreasesexpressionofnegativeregulatorsofTLR4pathways...

【 授权许可】

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