Regulatory mechanisms of cytokines and adhesion molecules gene expression by nuclear receptors: for the development of new anti-inflammatory drugs

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First, we examined the effects of progestins on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human vascular endothelial cells (Ecs). Immunocytochemical analysis revealed the presence of progesterone receptor (PgR) in HUVECs. Progesterone and R5020 clearly inhibited tumor necrosis factor (TNF)-α-activated expression of VCAM-1 protein and its mRNA in HUVECs, whereas medroxyprogesterone acetate (MPA) failed to do so. Electrophoretic mobility shift assays (EMSA) demonstrated that progesterone, but not MPA, inhibited DNA binding of NF-κB, which is critical for the inducible expression of VCAM-1. Since the expression of VCAM-1 is one of the earliest events occurred in atherogenic process, this adhesion molecule might be a target molecule for progesterone on vascular walls. The contrasting effects of progesterone and MPA seem clinically important, since MPA is a widely used progestin as the regimen of HRT.Second, we examined the effects of PPAR α activator fenofibrate and g … More lucocorticoid receptor (GR) activator dexamethasone on TNF-α-stimulated expression of IL-6 and VCAM-1 in Ecs, Both fenofibrate and dexamethasone reduced TNF-α-induced IL-6 production in human vascular Ecs, but only fenofibrate reduced TNF-α-stimulated VCAM-1 expression in these cells. Transient transfection of bovine aortic Ecs with an IL-6 promoter construct or a VCAM-1 promoter construct revealed that fenofibrate inhibited TNF-a-induced IL-6 promoter as well as VCAM-1 promoter activities, while dexamethasone inhibited only the former. EMSA demonstrated that both fenofibrate and dexamethasone reduced nuclear NF-κB-binding to its recognition site on the IL-6 promoter, but only fenofibrate reduced such binding to the VCAM-1 promoter. Thus, downregulation of NF-κB activity by PPARα occurs in both the IL-6 and VCAM-1 genes, whereas that by GR occurs only in the IL-6 gene in vascular Ecs. These results strongly suggest the existence of a target gene-specific mechanism for the nuclear receptor-mediated downregulation of NF-κB activity. Less