Print Email Facebook Twitter Macrophage-specific inhibition of NF-κB activation reduces foam-cell formation 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 BiologyBiomedical 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 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 Files To receive the publication files, please send an e-mail request to TNO Library.