Oxidized Low-Density Lipoprotein Loading of Macrophages Downregulates TLR-Induced Proinflammatory Responses in a Gene-Specific and Temporal Manner through Transcriptional Control.
J Immunol
; 199(6): 2149-2157, 2017 09 15.
Article
em En
| MEDLINE
| ID: mdl-28784845
ABSTRACT
Hypercholesterolemia is a key risk factor for atherosclerosis and leads to the uptake of native and oxidized low-density lipoprotein (oxLDL) by macrophages (MÏs) and foam cell formation. Inflammatory processes accompany MÏ foam cell formation in the artery wall, yet the relationship between MÏ lipid loading and their response to inflammatory stimuli remains elusive. We investigated proinflammatory gene expression in thioglycollate-elicited peritoneal MÏs, bone marrow-derived MÏs and dendritic cells, and RAW264.7 cells. Loading with oxLDL did not induce peritoneal MÏ apoptosis or modulate basal-level expression of proinflammatory genes. Upon stimulation of TLR4, the rapid induction of IFN-ß was inhibited in cells loaded with oxLDL, whereas the induction of other proinflammatory genes by TLR4 (LPS), TLR3 (polyriboinosinic-polyribocytidylic acid), TLR2 (Pam3CSK4), and TLR9 (CpG) remained comparable within the first 2 h. Subsequently, the expression of a subset of proinflammatory genes (e.g., IL-1ß, IL-6, CCL5) was reduced in oxLDL-loaded cells at the level of transcription. This phenomenon was partially dependent on NF erythroid 2-related factor 2 (NRF2) but not on nuclear liver X receptors α and ß (LXRα,ß), peroxisome proliferator-activated receptor-γ (PPARγ), and activating transcription factor 3 (ATF3). LPS-induced NF-κB reporter activity and intracellular signaling by NF-κB and MAPK pathways were comparable in oxLDL-loaded MÏs, yet the binding of p65/RelA (the prototypic NF-κB family member) was reduced at IL-6 and CCL5 promoters. This study revealed that oxLDL loading of MÏs negatively regulates transcription at late stages of TLR-induced proinflammatory gene expression and implicates epigenetic mechanisms such as histone deacetylase activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Macrófagos Peritoneais
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Aterosclerose
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Receptor 4 Toll-Like
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Células Espumosas
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Hipercolesterolemia
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Lipoproteínas LDL
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Macrófagos
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2017
Tipo de documento:
Article