Title
Macrophage-specific inhibition of NF-κB activation reduces foam-cell formation
Author
Ferreira, V.
van Dijk, K.W.
Groen, A.K.
Vos, R.M.
van der Kaa, J.
Gijbels, M.J.J.
Havekes, L.M.
Pannekoek, H.
TNO Kwaliteit van Leven
Publication year
2007
Abstract
Accumulation of lipid-laden macrophages is a hallmark of atherosclerosis. The relevance of the key transcription factor nuclear factor κB (NF-κB) for macrophage-derived foam-cell formation has not been unequivocally resolved. Transgenic mice lines were generated in which NF-κB activation is specifically inhibited in macrophages by overexpressing a trans-dominant, non-degradable form of IκBα (IκBα (32A/36A)) under control of the macrophage-specific SR-A promoter. Alanine substitution of serines 32 and 36 prevents degradation and retains the inactive NF-κB/IκBα (32A/36A) complex in the cytoplasm. Similarly, stable human THP1 monocytic cell lines were generated with integrated copies of IκBα (32A/36A) cDNA. Upon treatment with oxidized low-density lipoprotein (ox-LDL), murine peritoneal macrophages from transgenic IκBα (32A/36A) mice, as well as THP1/IκBα (32A/36A) clones, display decreased lipid loading after differentiation into macrophages. This is accompanied by increased expression of the transcription factors PPARγ and LXRα as well as of the major cholesterol-efflux transporter ABCA1. Paradoxically, mRNA expression of the 'lipid-uptake' receptor CD36 is also increased. Since the net result of these changes is reduction of foam-cell formation, it is proposed that under specific inhibition of NF-κB activation, ABCA1-mediated cholesterol efflux prevails over CD36-mediated lipid influx. © 2006 Elsevier Ireland Ltd. All rights reserved.
Subject
Biology
Biomedical Research
ABCA1 mediated cholesterol efflux
Foam cell formation
Macrophage specific inhibition of NF-κB, IκBα
ox-LDL-PPARγ-CD36 "feed-forward cycle"
I kappa B kinase alpha
immunoglobulin enhancer binding protein
article
cell differentiation
cell line
cell specificity
controlled study
cytoplasm
foam cell
gene expression
human
human cell
lipid oxidation
lipid transport
monocyte
mouse
nonhuman
peritoneum cell
priority journal
protein degradation
protein expression
transgenic mouse
Animals
Antigens, CD36
ATP-Binding Cassette Transporters
Cell Line
DNA-Binding Proteins
Foam Cells
Humans
I-kappa B Proteins
Lipoproteins, LDL
Macrophages
Mice
Mice, Inbred C57BL
NF-kappa B
PPAR gamma
Receptors, Cytoplasmic and Nuclear
Scavenger Receptors, Class A
To reference this document use:
http://resolver.tudelft.nl/uuid:04deac64-397b-4ec9-bd43-0e5bfdefaf0e
DOI
https://doi.org/10.1016/j.atherosclerosis.2006.07.018
TNO identifier
240006
ISSN
0021-9150
Source
Atherosclerosis, 192 (2), 283-290
Document type
article