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PPAR and GR Differentially Down-Regulate the Expression of Nuclear Factor-B-Responsive Genes in Vascular Endothelial Cells

Department of Molecular Medicine, Osaka University Graduate School of Medicine (C-4), Suita, Osaka 565-0871, Japan

Address all correspondence and requests for reprints to: Dr. Soji Kasayama, Department of Molecular Medicine, Osaka University Graduate School of Medicine (C-4), 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: kasayama{at}imed3.med.osaka-u.ac.jp

The antiinflammatory action of glucocorticoids is mediated partly by the inhibition of the expression of several cytokines and adhesion molecules. Some activators for nuclear receptors other than the GR have also been shown to inhibit the expression of these inflammatory molecules, although their molecular mechanisms remain unidentified. We therefore examined the effects of the PPAR activator fenofibrate and the GR activator dexamethasone on TNF-stimulated expression of IL-6 and vascular cell adhesion molecule-1 in vascular endothelial cells. Both fenofibrate and dexamethasone reduced TNF-induced IL-6 production in human vascular endothelial cells, but only fenofibrate reduced TNF-stimulated vascular cell adhesion molecule-1 expression in these cells. Transient transfection of bovine aortic endothelial cells with an IL-6 promoter construct or a vascular cell adhesion molecule-1 promoter construct revealed that fenofibrate inhibited TNF-induced IL-6 promoter as well as vascular cell adhesion molecule-1 promoter activities, whereas dexamethasone inhibited only the former. EMSA demonstrated that both fenofibrate and dexamethasone reduced nuclear factor-B binding to its recognition site on the IL-6 promoter, but only fenofibrate reduced such binding to the vascular cell adhesion molecule-1 promoter. Thus, down-regulation of nuclear factor-B activity by PPAR occurs in both the IL-6 and vascular cell adhesion molecule-1 genes, whereas that by GR occurs only in the IL-6 gene in vascular endothelial cells. These results strongly suggest the existence of a target gene-specific mechanism for the nuclear receptor-mediated down-regulation of nuclear factor-B activity.

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