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ApoE Production in Human Monocytes and Its Regulation by Inflammatory Cytokines.doc

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ApoE Production in Human Monocytes and Its Regulation by Inflammatory Cytokines

ApoEProductioninHumanMonocytesandIts RegulationbyInflammatoryCytokines StenBraesch-Andersen1*,StaffanPaulie1,ChristianSmedman2,SohelMia3,MakikoKumagai-Braesch4 1Mabtech, Nacka Strand, Sweden, 2Mabtech and Center for Molecular Medicine, Infectious Diseases Unit L8:01, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, 3Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm,Sweden,4MabtechandCLINTEC,DivisionofTransplantationSurgery,KarolinskaInstitutet,Stockholm,Sweden Abstract TheapoEproductionbytissuemacrophagesiscrucialforthepreventionofatherosclerosisandtheaimofthisstudywasto further elucidate how this apolipoprotein is regulated by cytokines present during inflammation. Here we studied apoE production in peripheral blood mononuclear cells (PBMC) and analysis was made with a newly developed apoE ELISpot assay.InPBMC,apoEsecretionwasrestrictedtomonocyteswithclassical(CD14 CD162)andintermediate(CD14+CD16 ) monocytesbeingthemainproducers.Asearlierdescribedformacrophages,productionwasstronglyupregulatedbyTGF-b anddownregulatedbybacteriallipopolysaccharide(LPS)andtheinflammatorycytokinesIFN-c,TNF-aandIL-1b.Wecould here show that a similar down-regulatory effect was also observed with the type I interferon, IFN-a, while IL-6, often regardedasoneofthemoreprominentinflammatorycytokines,didnotaffectTGF-b-inducedapoEproduction.TheTNF-a inhibitorEnbrelcouldpartlyblockthedown-regulatoryeffectofIFN-c,IFN-aandIL-1b,indicatingthatinhibitionofapoEby thesecytokinesmaybedependentonorsynergizewithTNF-a.Othercytokinestested,IL-2,IL-4,IL-12,IL-13,IL-17AandIL- 23, had no inhibitory effect on apoE production. In contrast to the effect on monocytes, apoE production by primary hepatocytesandthehepatomacelllineHepG2wasmoreorlessunaffectedbytreatmentwithcytokinesorLPS. ++ + Citation:Braesch-AndersenS,PaulieS,SmedmanC,MiaS,Kumagai-BraeschM(2013)ApoEProductioninHum