Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-κB to DNA and the subsequent expression of tumor necrosis factor-α and interleukin-1β in macrophages

Abstract

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)-κB 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-κB. However, the LPS-induced response to NF-κB 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, 7β- 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-α and IL-1β 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.