Retinoids Inhibit Interleukin-12 Production in Macrophages through Physical Associations of Retinoid X Receptor and NF B

Wistar Institute, Filadelfia, Pennsylvania, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 04/1999; 274(12):7674-80. DOI: 10.1074/jbc.274.12.7674
Source: PubMed


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.

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    International Reviews Of Immunology 10/2014; 34(1). DOI:10.3109/08830185.2014.969421 · 4.10 Impact Factor
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    • "Another study demonstrated that retinoids slow down progression of renal disease by suppressing important mediators such as angiotensin II, endothelin and TGF-β in an anti-Thy1.1 nephritis rat model [114]. Moreover, recent studies have indicated that retinoids suppress NF-κB and AP-1 in non-diabetic nephropathy [115,116]. Thus, RARs may have additional renoprotective functions through the transcriptional control of podocyte-specific proteins and pro-inflammatory cytokines that are know to further escalate pathogenic cascades in the kidney. "
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