title: Oxidized Low-Density Lipoprotein (OxLDL)-Treated Dendritic Cells Promote Activation of T Cells in Human Atherosclerotic Plaque and Blood, Which Is Repressed by Statins: microRNA let-7c Is Integral to the Effect.
abstract: Activated T cells and dendritic cells (DCs) are colocalized in atherosclerotic plaques in association with plaque rupture. Oxidized low-density lipoprotein (oxLDL) promotes immune activation and inflammation. We studied the effects of statins (atorvastatin and simvastatin) on human DC maturation and T-cell activation.
  
  
  
  Human peripheral blood monocytes were differentiated to DCs and stimulated with oxLDL. T cells were isolated from carotid endarterectomy specimens from patients undergoing carotid endarterectomy or from healthy individuals. Naïve T cells were cocultured with pretreated DCs. The effects of statin were studied. OxLDL induced DC maturation and T-cell activation. OxLDL induced atherogenic heat shock proteins (HSP) 60 and 90 and decreased potentially atheroprotective heat shock protein 27, effects restored by atorvastatin. T cells exposed to oxLDL-treated DCs produced interferon-γ and interleukin (IL)-17. Atorvastatin and simvastatin suppressed the DC maturation showing lower expression of CD80, CD83, and CD86, and limited their production of tumor necrosis factor-α, IL-1β and IL-6, and increased transforming growth factor-β and IL-10 secretion. Statin-treated DCs inhibited Th1 and/or Th17 polarization by downregulation of transcriptional factors T-bet and RORγt expression, and induced T regulatory cells with IL-10 production. OxLDL-induced miRNA let7c and phosphorylation of Akt and ERK were repressed by statins. Let-7c had a pivotal role in mediating effect of oxLDL. Experiments on T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar results.
  
  
  
  Statins repress human DC maturation induced by oxLDL, limit T-cell activation, and repress an atherogenic heat shock protein profile and promote induction of T regulatory cells. MicroRNA let-7c is integral to the effects.
authors.affiliation: Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden johan.frostegard@ki.se anquan.liu@ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Frostegård
authors.affiliation: Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jitong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Yan
authors.affiliation: Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden johan.frostegard@ki.se anquan.liu@ki.se.
authors.forename: Anquan
authors.initials: A
authors.lastname: Liu
mesh_terms: D000069059:Atorvastatin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D018834:Chaperonin 60 / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D016894:Endarterectomy, Carotid; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000187:drug effects / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000276:immunology; D006360:Heat-Shock Proteins; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053583:Interleukin-1beta / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D035683:MicroRNAs / Q000187:drug effects* / Q000276:immunology; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000276:immunology; D018832:Molecular Chaperones; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology; D020825:T-Box Domain Proteins / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D018834:Chaperonin 60; D055551:HSP27 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C057725:HSPB1 protein, human; C060293:HSPD1 protein, human; D006360:Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C508585:IL1B protein, human; C508600:IL6 protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C487931:mirnlet7 microRNA, human; C099252:oxidized low density lipoprotein; D007371:Interferon-gamma; D000069059:Atorvastatin; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: T cells; atherosclerosis; dendritic cells; immune system; microRNA; oxidized low‐density lipoprotein; statin