Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-γ and nuclear factor-κB

Wol Chung Su Wol Chung, Yun Kang Bok Yun Kang, Hyun Kim Seung Hyun Kim, Kim Pak Youngmi Kim Pak, D. Cho, G. Trinchieri, Sung Kim Tae Sung Kim

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Lipopolysaccharide (LPS) increases the production of interleukin-12 (IL-12) from mouse macrophages via a κB site within the IL-12 p40 promoter. In this study, we found that oxidized low density lipoprotein (oxLDL) inhibited this LPS-stimulated production of IL-12 in a dose-dependent manner while native LDL did not. OxLDL inhibited p40 promoter activation in monocytic RAW264.7 cells transiently transfected with p40 promoter/reporter constructs, and the repressive effect mapped to a region in the p40 promoter containing a binding site for nuclear factor-κB (NF-κB) (p40-κB). Activation of macrophages by LPS in the presence of ox-LDL resulted in markedly reduced binding to the κB site, as demonstrated by the electrophoretic mobility shift assays. In contrast, native LDL did not inhibit the IL-12 p40 promoter activation and NF-κB binding to the κB sites, suggesting that oxidative modification of LDL was crucial for the inhibition of NF-κB-mediated IL-12 production. 9-Hydroxyoctadecadienoic acid, a major oxidized lipid component of oxLDL, significantly inhibited IL-12 production in LPS-stimulated mouse macrophages and also suppressed NF-κB-mediated activation in IL-12 p40 promoter. The NF-κB components p50 and p65 directly bound peroxisome proliferator-activated receptor-γ (PPAR-γ) in vitro. In cotransfections of CV-1 and HeLa cells, PPAR-γ inhibited the NF-κB transactivation in an oxLDL-dependent manner. From these results, we propose that oxLDL-mediated suppression of the IL-12 production from LPS-activated mouse macrophages may, at least in part, involve both inhibition of the NF-κB-DNA interactions and physical interactions between NF-κB and PPAR-γ.

Original languageEnglish
Pages (from-to)32681-32687
Number of pages7
JournalJournal of Biological Chemistry
Issue number42
Publication statusPublished - 2000 Oct 20
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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