Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society | |
Induction of endotoxin tolerance in vivo inhibits activation of IRAK4 and increases negative regulators IRAK‐M, SHIP‐1, and A20 | |
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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