Bile acids PKA‐dependently induce a switch of the IL‐10/IL‐12 ratio and reduce proinflammatory capability of human macrophages

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

关键词: TLR;    LPS;    TLC;    cytokines;    TGR5;   

DOI  :  10.1189/jlb.0812396

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Thatcholestaticconditionsareaccompaniedbyanenhancedsusceptibilitytobacterialinfectioninhumanandanimalmodelsisaknownphenomenon.Thiscorrelateswiththeobservationthatbileacidshavesuppressiveeffectsoncellsofinnateandadaptiveimmunity.Thepresentstudyprovidesevidencethatinhumanmacrophages,bileacidsinhibittheLPS‐inducedexpressionofproinflammatorycytokineswithoutaffectingtheexpressionoftheanti‐inflammatorycytokineIL‐10.ThisresultsinamacrophagephenotypethatischaracterizedbyanincreasedIL‐10/IL‐12ratio.Correspondingly,bileacidssuppressbasalphagocyticactivityofhumanmacrophages.TheseeffectsofbileacidscanbemimickedbycAMP,whichispresumablyinducedTGR5‐dependently.Thedataprovidedfurthersuggestthatinprimaryhumanmacrophages,modulationofthemacrophageresponsetowardLPSbybileacidsinvolvesactivationofCREB,disturbednucleartranslocationofNF‐κB,andPKA‐dependentenhancementofLPS‐inducedcFosexpression.TheincreaseincFosexpressionisparalleledbyanenhancedformationofaproteincomplexcomprisingcFosandthep65subunitofNF‐κB.Insummary,thedataprovidedsuggestthatinhumanmacrophages,bileacidsinduceananti‐inflammatoryphenotypecharacterizedbyanincreasedIL‐10/IL‐12ratioviaactivationofPKAandthereby,preventtheiractivationasclassicallyactivatedmacrophages.Thisbileacid‐inducedmodulationofmacrophagefunctionmayalsoberesponsiblefortheexperimentallyandclinicallyobservedanti‐inflammatoryandimmunosuppressiveeffectsofbileacids...

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