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PMID:16938301

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Citation

Ferreira, V, van Dijk, KW, Groen, AK, Vos, RM, van der Kaa, J, Gijbels, MJ, Havekes, LM and Pannekoek, H (2007) Macrophage-specific inhibition of NF-kappaB activation reduces foam-cell formation. Atherosclerosis 192:283-90

Abstract

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.

Links

PubMed Online version:10.1016/j.atherosclerosis.2006.07.018

Keywords

ATP-Binding Cassette Transporters/biosynthesis; Animals; Antigens, CD36/biosynthesis; Cell Line; DNA-Binding Proteins/biosynthesis; Foam Cells/physiology; Humans; I-kappa B Proteins/genetics; I-kappa B Proteins/physiology; Lipoproteins, LDL/metabolism; Macrophages/drug effects; Macrophages/physiology; Mice; Mice, Inbred C57BL; NF-kappa B/antagonists & inhibitors; Orphan Nuclear Receptors; PPAR gamma/biosynthesis; Receptors, Cytoplasmic and Nuclear/biosynthesis; Scavenger Receptors, Class A/biosynthesis

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NFKB1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000305: curator inference used in manual assertion

GO:0005634

P

Seeded From UniProt

complete

HUMAN:NFKB1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NFKB1

enables

GO:0000976: transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:IKBA

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IKBA

involved_in

GO:0032270: positive regulation of cellular protein metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IKBA

involved_in

GO:0010888: negative regulation of lipid storage

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IKBA

involved_in

GO:0010875: positive regulation of cholesterol efflux

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IKBA

involved_in

GO:0010745: negative regulation of macrophage derived foam cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IKBA

involved_in

GO:0007253: cytoplasmic sequestering of NF-kappaB

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IKBA

part_of

GO:0033256: I-kappaB/NF-kappaB complex

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NFKB1

involved_in

GO:0010884: positive regulation of lipid storage

ECO:0000305: curator inference used in manual assertion

GO:0005634

P

Seeded From UniProt

complete

HUMAN:NFKB1

involved_in

GO:0010744: positive regulation of macrophage derived foam cell differentiation

ECO:0000305: curator inference used in manual assertion

GO:0005634

P

Seeded From UniProt

complete

HUMAN:NFKB1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NFKB1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000305: curator inference used in manual assertion

GO:0005634

P

Seeded From UniProt

complete

HUMAN:NFKB1

involved_in

GO:0032269: negative regulation of cellular protein metabolic process

ECO:0000305: curator inference used in manual assertion

GO:0005634

P

Seeded From UniProt

complete

HUMAN:NFKB1

involved_in

GO:0032375: negative regulation of cholesterol transport

ECO:0000305: curator inference used in manual assertion

GO:0005634

P

Seeded From UniProt

complete

HUMAN:NFKB1

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NFKB1

part_of

GO:0033256: I-kappaB/NF-kappaB complex

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete


See also

References

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