Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappa B to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1 beta 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)-kappa B 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-KB, However, the LPS-induced response to NF-kappa B 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-l-binding were seen with the oxysterols, 7 beta-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-1 beta 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.