Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein.
Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8. This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.
Brand
K
K
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University Munich, Germany.
Eisele
T
T
Kreusel
U
U
Page
M
M
Page
S
S
Haas
M
M
Gerling
A
A
Kaltschmidt
C
C
Neumann
F J
FJ
Mackman
N
N
Baeurele
P A
PA
Walli
A K
AK
Neumeier
D
D
D000975:Antioxidants / Q000494:pharmacology; D001161:Arteriosclerosis / Q000209:etiology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000502:physiology; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000502:physiology; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014158:Transcription, Genetic / Q000187:drug effects
D000975:Antioxidants; D016209:Interleukin-8; D008077:Lipoproteins, LDL; D009097:Multienzyme Complexes; D016328:NF-kappa B; C099252:oxidized low density lipoprotein; D006861:Hydrogen Peroxide; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex