Abstract
Background:
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.
Methods and results:
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.
Conclusions:
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.
Keywords:
T cells; atherosclerosis; dendritic cells; immune system; microRNA; oxidized low‐density lipoprotein; statin.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
MeSH terms
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Atorvastatin / pharmacology
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Cell Differentiation / drug effects
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Chaperonin 60 / drug effects
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Chaperonin 60 / immunology
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Endarterectomy, Carotid
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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HSP27 Heat-Shock Proteins / drug effects
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HSP27 Heat-Shock Proteins / immunology
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HSP90 Heat-Shock Proteins / drug effects
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HSP90 Heat-Shock Proteins / immunology
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Heat-Shock Proteins
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Interferon-gamma / drug effects
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Interferon-gamma / immunology
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Interleukin-17 / immunology
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Interleukin-1beta / drug effects
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Interleukin-1beta / immunology
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Interleukin-6 / immunology
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Lipoproteins, LDL / pharmacology*
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Lymphocyte Activation / drug effects*
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Lymphocyte Activation / immunology
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MicroRNAs / drug effects*
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MicroRNAs / immunology
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Mitochondrial Proteins / drug effects
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Mitochondrial Proteins / immunology
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Molecular Chaperones
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Nuclear Receptor Subfamily 1, Group F, Member 3 / drug effects
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Phosphorylation / drug effects
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Plaque, Atherosclerotic / immunology*
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Simvastatin / pharmacology
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T-Box Domain Proteins / drug effects
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T-Box Domain Proteins / metabolism
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Tumor Necrosis Factor-alpha / drug effects
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Tumor Necrosis Factor-alpha / immunology
Substances
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Chaperonin 60
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HSP27 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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HSPB1 protein, human
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HSPD1 protein, human
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Heat-Shock Proteins
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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IL1B protein, human
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IL6 protein, human
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Interleukin-17
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Interleukin-1beta
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Interleukin-6
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Lipoproteins, LDL
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MicroRNAs
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Mitochondrial Proteins
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Molecular Chaperones
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RORC protein, human
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T-Box Domain Proteins
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T-box transcription factor TBX21
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TNF protein, human
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Tumor Necrosis Factor-alpha
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mirnlet7 microRNA, human
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oxidized low density lipoprotein
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Interferon-gamma
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Atorvastatin
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Simvastatin
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases