Xu X, Otsuki M, Saito H, Sumitani S, Yamamoto H, Asanuma N, Kouhara H, Kasayama S
Department of Molecular Medicine, Osaka University Graduate School of Medicine (C-4), Suita, Osaka 565-0871, Japan.
Endocrinology. 2001 Aug;142(8):3332-9. doi: 10.1210/endo.142.8.8340.
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 PPARalpha activator fenofibrate and the GR activator dexamethasone on TNFalpha-stimulated expression of IL-6 and vascular cell adhesion molecule-1 in vascular endothelial cells. Both fenofibrate and dexamethasone reduced TNFalpha-induced IL-6 production in human vascular endothelial cells, but only fenofibrate reduced TNFalpha-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 TNFalpha-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-kappaB 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-kappaB activity by PPARalpha 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-kappaB activity.
糖皮质激素的抗炎作用部分是通过抑制多种细胞因子和黏附分子的表达来介导的。一些糖皮质激素受体（GR）以外的核受体激活剂也已被证明可抑制这些炎症分子的表达，尽管它们的分子机制尚不清楚。因此，我们研究了过氧化物酶体增殖物激活受体α（PPARα）激活剂非诺贝特和GR激活剂地塞米松对肿瘤坏死因子α（TNFα）刺激的血管内皮细胞中白细胞介素-6（IL-6）和血管细胞黏附分子-1表达的影响。非诺贝特和地塞米松均降低了TNFα诱导的人血管内皮细胞中IL-6的产生，但只有非诺贝特降低了TNFα刺激的这些细胞中血管细胞黏附分子-1的表达。用IL-6启动子构建体或血管细胞黏附分子-1启动子构建体瞬时转染牛主动脉内皮细胞表明，非诺贝特抑制TNFα诱导的IL-6启动子以及血管细胞黏附分子-1启动子活性，而地塞米松仅抑制前者。电泳迁移率变动分析（EMSA）表明，非诺贝特和地塞米松均降低了核因子κB与IL-6启动子上其识别位点的结合，但只有非诺贝特降低了其与血管细胞黏附分子-1启动子的结合。因此，PPARα对核因子κB活性的下调在IL-6和血管细胞黏附分子-1基因中均有发生，而GR介导的下调仅发生在血管内皮细胞的IL-6基因中。这些结果强烈提示存在一种核受体介导的核因子κB活性下调的靶基因特异性机制。
