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.
"Vitamin A increases the phagocytic capacity of macrophages  . All-trans-retinoic acid enhanced the secretion of proinflammatory cytokines like IL-1β and IL-6 by monocytes/macrophages  , though it was reported that all-trans-retinoic acid inhibited LPS-induced IL-12 and TNF-α production by mouse macrophages  . The cellular uptake of vitamin A from its retinol-binding protein 4 (RBP4)-bound circulating form is a homeostatic process. "
[Show abstract][Hide abstract] ABSTRACT: Macrophages are a functionally heterogeneous cell population that is mainly shaped by a variety of microenvironmental stimuli. Interferon γ (IFN-γ), interleukin-1β (IL-1β), and lipopolysaccharide (LPS) induce a classical activation of macrophages (M1), whereas IL-4 and IL-13 induce an alternative activation program in macrophages (M2). Reprogramming of intracellular metabolisms is required for the proper polarization and functions of activated macrophages. Similar to the Warburg effect observed in tumor cells, M1 macrophages increase glucose consumption and lactate release and decreased oxygen consumption rate. In comparison, M2 macrophages mainly employ oxidative glucose metabolism pathways. In addition, fatty acids, vitamins, and iron metabolisms are also related to macrophage polarization. However, detailed metabolic pathways involved in macrophages have remained elusive. Understanding the bidirectional interactions between cellular metabolism and macrophage functions in physiological and pathological situations and the regulatory pathways involved may offer novel therapies for macrophage-associated diseases.
International Reviews Of Immunology 10/2014; 34(1). DOI:10.3109/08830185.2014.969421 · 4.10 Impact Factor
"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
. 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. "
[Show abstract][Hide abstract] ABSTRACT: Nuclear receptors are a family of ligand-activated, DNA sequence-specific transcription factors that regulate various aspects of animal development, cell proliferation, differentiation, and homeostasis. The physiological roles of nuclear receptors and their ligands have been intensively studied in cancer and metabolic syndrome. However, their role in kidney diseases is still evolving, despite their ligands being used clinically to treat renal diseases for decades. This review will discuss the progress of our understanding of the role of nuclear receptors and their ligands in kidney physiology with emphasis on their roles in treating glomerular disorders and podocyte injury repair responses.
Cell and Bioscience 09/2012; 2(1):33. DOI:10.1186/2045-3701-2-33 · 3.63 Impact Factor
"We found that the RXR agonist significantly inhibited carrageenan-induced paw edema in mice and that this effect was significantly inhibited by both RXR antagonist and actinomycin D, an inhibitor of RNA synthesis. RXR binds the nuclear factor kappa B (NF-κB) components p50 and p65 and also inhibits NF-κB transactivation . Moreover, Uchimura et al.  have showed that the synthetic RXR agonist Ro47-5944 suppressed LPS-induced inducible nitric oxide synthesis (iNOS) and TNF-α mRNA expression. "
[Show abstract][Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) forms a heterodimeric DNA-binding complex with retinoid X receptors (RXRs). It has been reported that the effect of the PPAR agonist is reduced in hepatocyte RXR-deficient mice. Therefore, it is suggested that the endogenous RXR ligand is involved in the PPARγ agonist-induced anti-inflammatory effect. However, the participation of the RXR ligand in the PPARγ-induced anti-inflammatory effect is unknown. Here, we investigated the influence of RXR antagonist on the anti-inflammatory effect of PPARγ agonist pioglitazone in carrageenan test. In addition, we also examined the influence of PPAR antagonist on the anti-inflammatory effect induced by RXR agonist NEt-3IP. The RXR antagonist suppressed the antiedema effect of PPARγ agonist. In addition, the anti-inflammatory effect of RXR agonist was suppressed by PPARγ antagonist. PPARγ agonist-induced anti-inflammatory effects were reversed by the RXR antagonist. Thus, we showed that the endogenous RXR ligand might contribute to the PPARγ agonist-induced anti-inflammatory effect.
PPAR Research 12/2011; 2011:840194. DOI:10.1155/2011/840194 · 1.64 Impact Factor
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