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

J Clin Invest. 1996 Jul 1;98(1):78-89. doi: 10.1172/JCI118780.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA / metabolism*
  • DNA-Binding Proteins / metabolism
  • Gene Expression
  • Humans
  • Interleukin-1 / biosynthesis*
  • Interleukin-1 / genetics
  • Lipopolysaccharides / pharmacology
  • Lipoproteins, LDL / pharmacology*
  • Macrophages / drug effects*
  • Molecular Sequence Data
  • NF-kappa B / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Protein Binding / drug effects
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / biosynthesis
  • Serum Response Factor
  • Sterols / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics
  • ets-Domain Protein Elk-4


  • DNA-Binding Proteins
  • ELK4 protein, human
  • Interleukin-1
  • Lipopolysaccharides
  • Lipoproteins, LDL
  • NF-kappa B
  • Nuclear Proteins
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Serum Response Factor
  • Sterols
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • oxidized low density lipoprotein
  • ets-Domain Protein Elk-4
  • DNA