OXIDIZED LOW-DENSITY-LIPOPROTEIN INHIBITS LIPOPOLYSACCHARIDE-INDUCED BINDING OF NUCLEAR FACTOR-KAPPA-B TO DNA AND THE SUBSEQUENT EXPRESSIONOF 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 th e transcription factors nuclear factor (NF)-kappa B and AP-1 to DNA, T hese transcription factors are involved in the regulation of several g enes and expressed during activation of macrophages, for example by en dotoxin (LPS). OxLDL did not induce binding of NF-KB, However, the LPS -induced response to NF-kappa B was substantially reduced after preinc ubation 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 ef fect of oxLDL on the DNA-binding of AP-1, which might be mediated by t he oxysterol content of oxLDL. A decreased LPS-induced TNF-alpha and I L-1 beta mRNA and protein expression were found in macrophages incubat ed with oxLDL before LPS-exposure, These observations suggest that mac rophages that internalize extensively oxidized LDL are suppressed in t heir response to inflammatory stimulation.