Macrophage-specific inhibition of NF-kappaB activation reduces foam-cell formation.
Accumulation of lipid-laden macrophages is a hallmark of atherosclerosis. The relevance of the key transcription factor nuclear factor kappaB (NF-kappaB) for macrophage-derived foam-cell formation has not been unequivocally resolved. Transgenic mice lines were generated in which NF-kappaB activation is specifically inhibited in macrophages by overexpressing a trans-dominant, non-degradable form of IkappaBalpha (IkappaBalpha (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-kappaB/IkappaBalpha (32A/36A) complex in the cytoplasm. Similarly, stable human THP1 monocytic cell lines were generated with integrated copies of IkappaBalpha (32A/36A) cDNA. Upon treatment with oxidized low-density lipoprotein (ox-LDL), murine peritoneal macrophages from transgenic IkappaBalpha (32A/36A) mice, as well as THP1/IkappaBalpha (32A/36A) clones, display decreased lipid loading after differentiation into macrophages. This is accompanied by increased expression of the transcription factors PPARgamma and LXRalpha 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-kappaB activation, ABCA1-mediated cholesterol efflux prevails over CD36-mediated lipid influx.
Ferreira
Valérie
V
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. v.ferreira@amc.uva.nl <v.ferreira@amc.uva.nl>
van Dijk
Ko Willems
KW
Groen
Albert K
AK
Vos
Rogier M
RM
van der Kaa
Jos
J
Gijbels
Marion J J
MJ
Havekes
Louis M
LM
Pannekoek
Hans
H
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005487:Foam Cells / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D051117:Scavenger Receptors, Class A / Q000096:biosynthesis
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000605213:NR1H3 protein, human; C000606205:Nfkbia protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein; D000072000:NF-KappaB Inhibitor alpha