Proinflammatory effects of malondialdehyde in lymphocytes

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

关键词: lymphocytes;    malondialdehyde;    oxidative stress;    diabetes;    signaling pathways;    cytokines;   

DOI  :  10.1189/jlb.1211617

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Diabetesisaninflammatorydiseasepromotedbyalterationsinimmunecellfunction.AnimalstudyindicatesthatTcellsareimportantmediatorsofinflammationindiabetes.Lipidperoxidationbyreactiveoxygenspeciesleadstotheformationofhighlyreactivemalondialdehyde(MDA),andextensiveMDAisfoundindiabetes.However,thebiologicalfunctionsofMDAhavenotbeenstudiedyet.WehypothesizedthatincreasedMDA,asindiabetes,canregulateinflammatorycytokinesviaspecificsignalingpathways.Thiscouldthenresultinincreasedlymphocyteactivationandskewingaparticularinflammatorysubsettherebyexacerbatesdiabetescomplications.CommercialcytokineantibodyandRT2‐PCRarrayprofilingwereperformedwithJurkatTcellsgrownwithorwithoutMDA.Ingenuitypathwaysanalysis(IPA)andpharmacologicalinhibitorswereusedfornetworksandsignalingpathwayidentification,respectively.Forvalidation,real‐timePCR,RT‐PCR,andWesternblotswereperformed.MDAinducedsignificantincreasesin47keyproinflammatorymoleculessuchasIL‐25,IL‐6,IL‐8,ICAM‐1,andlightmRNAinJurkatTcellsandprimaryperipheralbloodlymphocytes(PBLCs).Asignificant2‐foldincreaseinserumMDAalsocorrelatedtheincreasedIL‐25andIL‐8mRNAinPBLCsofdiabeticpatients.PharmacologicalinhibitorstudiesshowedthatMDAinduceditseffectviap38MAPKandproteinkinaseCpathways.Furthermore,IPAuncovered5groupsofinflammatorynetworksandplacedourcandidategenesincanonicalIL‐6andNF‐κBsignalingpathwaysandalsosuggested5toxiclistsand3majortoxicfunctions,namelycardiotoxicity,hepatotoxicity,andnephrotoxicity.ThesenewresultssuggestthatMDAcanpromotelymphocyteactivationviainductionofinflammatorypathwaysandnetworks...

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