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

Research output: Contribution to journalArticle

295 Citations (Scopus)

Abstract

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
Volume275
Issue number42
DOIs
Publication statusPublished - 2000 Oct 20

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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