Sy. Na et al., Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NF kappa B, J BIOL CHEM, 274(12), 1999, pp. 7674-7680
Lipopolysaccharide (LPS) increases the production of interleukin-12 (IL-12)
from mouse macrophages via a kappa B site within the IL-12 p40 promoter. I
n this study, we found that retinoids inhibit this LPS-stimulated productio
n of IL-12 in a dose-dependent manner. The NF kappa B components p50 and p6
5 bound retinoid X receptor (RXR) in a ligand-independent manner in vitro,
and the interaction interfaces involved the p50 residues 1-245, the p65 res
idues 194-441, and the N-terminal A/B/C domains of RXR, Activation of macro
phages by LPS resulted in markedly enhanced binding activities to the kappa
B site, which significantly decreased upon addition of retinoids, as demon
strated by the electrophoretic mobility shift assays. In cotransfections of
CV-1 and HeLa cells, RXR also inhibited the NF kappa B transactivation in
a ligand-dependent manner, whereas a mutant RXR lacking the AF2 transactiva
tion domain, which serves as ligand-dependent binding sites for transcripti
on integrators SRC-1 and p300, was without any effect. In addition, coexpre
ssion of increasing amounts of SRC-1 or p300 relieved the retinoid-mediated
inhibition of the NF kappa B transactivation, From these results, we propo
se that retinoid-mediated suppression of the IL-12 production from LPS-acti
vated macrophages may involve both inhibition of the NF kappa B-DNA interac
tions and competitive recruitment of transcription integrators between NF k
appa B and RXR.