Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions betweenperoxisome proliferator-activated receptor-gamma and nuclear factor-kappa B
Sw. Chung et al., Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions betweenperoxisome proliferator-activated receptor-gamma and nuclear factor-kappa B, J BIOL CHEM, 275(42), 2000, pp. 32681-32687
Lipopolysaccharide (LPS) increases the production of interleukin-12 (IL-12)
from mouse macrophages via a kappaB site within the IL-12 p40 promoter. In
this study, we found that oxidized low density lipoprotein (oxLDL) inhibit
ed this LPS-stimulated production of IL-12 in a dose-dependent manner while
native LDL did not. OxLDL inhibited p40 promoter activation in monocytic R
AW264.7 cells transiently transfected with p40 promoter/reporter constructs
, and the repressive effect mapped to a region in the p40 promoter containi
ng a binding site for nuclear factor-kappaB (NF-kappaB) (p40-kappaB), Activ
ation of macrophages by LPS in the presence of oxLDL resulted in markedly r
educed binding to the kappaB site, as demonstrated by the electrophoretic m
obility shift assays. In contrast, native LDL did not inhibit the IL-12 p40
promoter activation and NF-kappaB binding to the kappaB sites, suggesting
that oxidative modification of LDL was crucial for the inhibition of NF-kap
paB-mediated IL-12 production. 9-Hydroxyoctadecadienoic acid, a major oxidi
zed lipid component of oxLDL, significantly inhibited IL-12 production in L
PS-stimulated mouse macrophages and also suppressed NF-kappaB-mediated acti
vation in IL-12 p40 promoter. The NF-kappaB components p50 and p65 directly
bound peroxisome proliferator-activated receptor-gamma (PPAP-gamma) in vit
ro, In cotransfections of CV-1 and HeLa cells, PPAR-gamma inhibited the NF-
kappaB transactivation in an oxLDL-dependent manner. From these results, we
propose that oxLDL-mediated suppression of the IL-12 production from LPS-a
ctivated mouse macrophages may, at least in part, involve both inhibition o
f the NF-kappaB-DNA interactions and physical interactions between NF-kappa
B and PPAR-gamma.