Caldenhoven E, Liden J, Wissink S, Van de Stolpe A, Raaijmakers J, Koenderman L, Okret S, Gustafsson J A, Van der Saag P T
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht.
Mol Endocrinol. 1995 Apr;9(4):401-12. doi: 10.1210/mend.9.4.7659084.
Glucocorticoids are efficient antiinflammatory agents, and their effects include transcriptional repression of several cytokines and adhesion molecules. Whereas glucocorticoids down-regulate the expression of genes relevant during inflammation, nuclear factor (NF)-kappa B/Rel proteins function as important positive regulators of these genes. The expression of intercellular adhesion molecule-1 (ICAM-1), which plays an essential role in recruitment and migration of leukocytes to sites of inflammation, is also down-regulated by glucocorticoids. We found that a functional NF-kappa B site in the ICAM-1 promoter, which can be activated by either 12-O-tetradecanoylphorbol-13-acetate or tumor necrosis factor-alpha (TNF alpha), is also the target for glucocorticoids. In this report we present evidence that the ligand-activated glucocorticoid receptor (GR) is able to repress RelA-mediated activation of the ICAM-1 NF-kappa B site. Conversely, transcriptional activation by GR via a glucocorticoid response element is specifically repressed by RelA, but not by other NF-kappa B/Rel family members. Mutational analysis of GR demonstrates that the DNA binding domain and the ligand binding domain are required for the functional repression of NF-kappa B activation. Despite the importance of the DNA binding domain, we found that the transcriptional repression of NF-kappa B, mediated by GR, is not caused by binding of GR to the ICAM-1 NF-kappa B element, but by a physical interaction between the GR and RelA protein. The repressive effect of GR on NF-kappa B-mediated activation was not shared by other steroid/thyroid receptors. Only the progesterone receptor, which belongs to the same subfamily as GR and which possesses high homology with GR, was able to repress NF-kappa B-mediated transcription. These studies highlight a possible molecular mechanism that can explain the antiinflammatory effects of glucocorticoid treatment during inflammation.
糖皮质激素是有效的抗炎剂，其作用包括对多种细胞因子和黏附分子的转录抑制。虽然糖皮质激素会下调炎症相关基因的表达，但核因子（NF）-κB/Rel蛋白却是这些基因的重要正向调节因子。细胞间黏附分子-1（ICAM-1）在白细胞募集和向炎症部位迁移过程中起关键作用，其表达也受到糖皮质激素的下调。我们发现，ICAM-1启动子中一个可被12-O-十四烷酰佛波醇-13-乙酸酯或肿瘤坏死因子-α（TNFα）激活的功能性NF-κB位点，也是糖皮质激素的作用靶点。在本报告中，我们提供证据表明，配体激活的糖皮质激素受体（GR）能够抑制RelA介导的ICAM-1 NF-κB位点的激活。相反，GR通过糖皮质激素反应元件的转录激活会被RelA特异性抑制，但不会被其他NF-κB/Rel家族成员抑制。对GR的突变分析表明，DNA结合结构域和配体结合结构域是NF-κB激活功能抑制所必需的。尽管DNA结合结构域很重要，但我们发现，GR介导的NF-κB转录抑制并非由GR与ICAM-1 NF-κB元件的结合引起，而是由GR与RelA蛋白之间的物理相互作用导致。GR对NF-κB介导的激活的抑制作用并非其他类固醇/甲状腺受体所共有。只有与GR属于同一亚家族且与GR具有高度同源性的孕激素受体能够抑制NF-κB介导的转录。这些研究突出了一种可能的分子机制，该机制可以解释糖皮质激素治疗在炎症期间的抗炎作用。
