Immunomodulatory and immunotoxic effects of bilirubin: molecular mechanisms

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

关键词: unconjugated bilirubin;    p38MAPK;    CD95;    Bax;    oxidative stress;   

DOI  :  10.1189/jlb.0211070

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

TheimmunomodulatoryandimmunotoxiceffectsofpurifiedUCBhavenotbeenevaluatedpreviouslyatclinicallyrelevantUCBconcentrationsandUCB:BSAratios.TodelineatethemolecularmechanismofUCB‐inducedimmunomodulation,immunecellswereexposedtoclinicallyrelevantconcentrationsofUCB.ItinhibitedLPS‐inducedBcellproliferationandcytokineproductionfromsplenicmacrophages.UCB(≥25μM)wastoxictounfractionatedsplenocytes,splenicTcells,Bcells,macrophages,LPS‐stimulatedCD19+Bcells,humanPBMCs,andRBCs.PurifiedUCBalsowasfoundtobetoxictosplenocytesandhumanPBMCs.UCBinducednecrosisandapoptosisinsplenocytes.UCBactivatedtheextrinsicandintrinsicpathwaysofapoptosis,asreflectedbythemarkers,suchasCD95,caspase‐8,Bax,MMP,cytoplasmicCa+2,caspase‐3,andDNAfragmentation.UCBdepletedGSHandactivatedp38MAPK.NAC,caspaseinhibitors,andp38MAPKinhibitorattenuatedtheUCB‐inducedapoptosis.Invivoadministrationof≥25mg/kbwUCBinducedatrophyofspleen,depletionofbonemarrowcells,andleukopeniaanddecreasedlymphocytecountandtheTandBcellresponsetomitogens.UCBadministrationtomiceledtoinductionofoxidativestress,activationofp38MAPK,andcelldeathinsplenocytes.TheseparameterswereattenuatedbytheinjectionofNACandthep38MAPKinhibitor.OurresultsdemonstrateforthefirsttimethatclinicallyrelevantconcentrationsofUCBinduceapoptosisandnecrosisinimmunecellsbydepletingcellularGSH.Thesefindingsshouldproveusefulinunderstandingtheimmunosuppressionassociatedwithhyperbilirubinemia...

【 授权许可】

CC BY