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Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB.

TitleRetinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB.
Publication TypeJournal Article
Year of Publication1999
AuthorsNa SY, Kang BY, Chung SW, Han SJ, Ma X, Trinchieri G, Im SY, Lee JW, Kim TS
JournalJ Biol Chem
Volume274
Issue12
Pagination7674-80
Date Published1999 Mar 19
ISSN0021-9258
KeywordsAnimals, Cell Line, Female, Interleukin-12, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred DBA, NF-kappa B, Promoter Regions, Genetic, Protein Binding, Receptors, Retinoic Acid, Retinoid X Receptors, Retinoids, Spleen, Transcription Factors, Transcription, Genetic
Abstract

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 retinoids inhibit this LPS-stimulated production of IL-12 in a dose-dependent manner. The NFkappaB components p50 and p65 bound retinoid X receptor (RXR) in a ligand-independent manner in vitro, and the interaction interfaces involved the p50 residues 1-245, the p65 residues 194-441, and the N-terminal A/B/C domains of RXR. Activation of macrophages by LPS resulted in markedly enhanced binding activities to the kappaB site, which significantly decreased upon addition of retinoids, as demonstrated by the electrophoretic mobility shift assays. In cotransfections of CV-1 and HeLa cells, RXR also inhibited the NFkappaB transactivation in a ligand-dependent manner, whereas a mutant RXR lacking the AF2 transactivation domain, which serves as ligand-dependent binding sites for transcription integrators SRC-1 and p300, was without any effect. In addition, coexpression of increasing amounts of SRC-1 or p300 relieved the retinoid-mediated inhibition of the NFkappaB transactivation. From these results, we propose that retinoid-mediated suppression of the IL-12 production from LPS-activated macrophages may involve both inhibition of the NFkappaB-DNA interactions and competitive recruitment of transcription integrators between NFkappaB and RXR.

DOI10.1074/jbc.274.12.7674
Alternate JournalJ Biol Chem
PubMed ID10075655

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