Reichardt H M, Tuckermann J P, Göttlicher M, Vujic M, Weih F, Angel P, Herrlich P, Schütz G
Division of Molecular Biology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
EMBO J. 2001 Dec 17;20(24):7168-73. doi: 10.1093/emboj/20.24.7168.
The glucocorticoid receptor (GR) acts both as a transcription factor itself on genes carrying GR response elements (GREs) and as a modulator of other transcription factors. Using mice with a mutation in the GR, which cannot activate GRE promoters, we examine whether the important anti-inflammatory and immune suppressive functions of glucocorticoids (GCs) can be established in this in vivo animal model. We find that most actions are indeed exerted in the absence of the DNA-binding ability of the GR: inhibition of the inflammatory response of locally irritated skin and of the systemic response to lipopolysaccharides. GCs repress the expression and release of numerous cytokines both in vivo and in isolated primary macrophages, thymocytes and CD4(+) splenocytes. A transgenic reporter gene controlled by NF-kappa B exclusively is also repressed, suggesting that protein- protein interaction with other transcription factors such as NF-kappa B forms the basis of the anti-inflammatory activity of GR. The only defect of immune suppression detected so far concerns the induced apoptosis of thymocytes and T lymphocytes.
糖皮质激素受体（GR）本身作为一种转录因子作用于携带GR反应元件（GRE）的基因，同时也是其他转录因子的调节剂。我们利用GR发生突变而无法激活GRE启动子的小鼠，来研究在这种体内动物模型中糖皮质激素（GCs）重要的抗炎和免疫抑制功能是否能够确立。我们发现，大多数作用确实是在GR缺乏DNA结合能力的情况下发挥的：抑制局部受刺激皮肤的炎症反应以及对脂多糖的全身反应。GCs在体内以及分离的原代巨噬细胞、胸腺细胞和CD4(+)脾细胞中均能抑制多种细胞因子的表达和释放。一个仅由NF-κB控制的转基因报告基因也受到抑制，这表明与其他转录因子如NF-κB的蛋白质-蛋白质相互作用构成了GR抗炎活性的基础。迄今为止检测到的免疫抑制的唯一缺陷涉及胸腺细胞和T淋巴细胞的诱导凋亡。
