Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages.
A large body of evidence suggests that oxidized LDL (oxLDL) has a role in atherogenesis. One effect is the impact on macrophage function. We have studied the effects of oxLDL and oxysterols on the binding of the transcription factors nuclear factor (NF)-kappaB and AP-1 to DNA. These transcription factors are involved in the regulation of several genes and expressed during activation of macrophages, for example by endotoxin (LPS). OxLDL did not induce binding of NF-kappaB. However, the LPS-induced response to NF-kappaB was substantially reduced after preincubation with oxLDL. Medium and highly oxidized LDL also decreased the constitutive DNA-binding of AP-1. Similar effects on AP-1-binding were seen with the oxysterols, 7beta-hydroxycholesterol, 24- hydroxy-, 25-hydroxy-, and 27-hydroxy-cholesterol. Our data therefore suggest an effect of oxLDL on the DNA-binding of AP-1, which might be mediated by the oxysterol content of oxLDL. A decreased LPS-induced TNF-alpha and IL-1beta mRNA and protein expression were found in macrophages incubated with oxLDL before LPS-exposure. These observations suggest that macrophages that internalize extensively oxidized LDL are suppressed in their response to inflammatory stimulation.
Ohlsson
B G
BG
The Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, University of Göteborg, Sweden.
Englund
M C
MC
Karlsson
A L
AL
Knutsen
E
E
Erixon
C
C
Skribeck
H
H
Liu
Y
Y
Bondjers
G
G
Wiklund
O
O
D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D026362:Serum Response Factor; D013261:Sterols / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D050808:ets-Domain Protein Elk-4
D004268:DNA-Binding Proteins; C494193:ELK4 protein, human; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D026362:Serum Response Factor; D013261:Sterols; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D050808:ets-Domain Protein Elk-4; D004247:DNA