Macrophage-specific inhibition of NF-κB activation reduces foam-cell formation
article
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.
Topics
Biomedical ResearchABCA1 mediated cholesterol effluxFoam cell formationMacrophage specific inhibition of NF-κB, IκBαox-LDL-PPARγ-CD36 "feed-forward cycle"I kappa B kinase alphaimmunoglobulin enhancer binding proteinarticlecell differentiationcell linecell specificitycontrolled studycytoplasmfoam cellgene expressionhumanhuman celllipid oxidationlipid transportmonocytemousenonhumanperitoneum cellpriority journalprotein degradationprotein expressiontransgenic mouseAnimalsAntigens, CD36ATP-Binding Cassette TransportersCell LineDNA-Binding ProteinsFoam CellsHumansI-kappa B ProteinsLipoproteins, LDLMacrophagesMiceMice, Inbred C57BLNF-kappa BPPAR gammaReceptors, Cytoplasmic and NuclearScavenger Receptors, Class A
TNO Identifier
240006
ISSN
00219150
Source
Atherosclerosis, 192(2), pp. 283-290.
Pages
283-290
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