Newton Robert
Department of Cell Biology and Anatomy, Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Eur J Pharmacol. 2014 Feb 5;724:231-6. doi: 10.1016/j.ejphar.2013.05.035. Epub 2013 Jun 7.
Despite being the most effective anti-inflammatory treatment for chronic inflammatory diseases, the mechanisms by which glucocorticoids (corticosteroids) effect repression of inflammatory gene expression remain incompletely understood. Direct interaction of the glucocorticoid receptor (NR3C1) with inflammatory transcription factors to repress transcriptional activity, i.e. transrepression, represents one mechanism of action. However, transcriptional activation, or transactivation, by NR3C1 also represents an important mechanism of glucocorticoid action. Glucocorticoids rapidly and profoundly increase expression of multiple genes, many with properties consistent with the repression of inflammatory gene expression. For example: the dual specificity phosphatase, DUSP1, reduces activation of mitogen-activated protein kinases; glucocorticoid-induced leucine zipper (TSC22D3) represses nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) transcriptional responses; inhibitor of κBα (NFKBIA) inhibits NF-κB; tristraprolin (ZFP36) destabilises and translationally represses inflammatory mRNAs; CDKN1C, a cell cycle regulator, may attenuate JUN N-terminal kinase signalling; and regulator of G-protein signalling 2 (RGS2), by reducing signalling from Gαq-linked G protein-coupled receptors (GPCRs), is bronchoprotective. While glucocorticoid-dependent transrepression can co-exist with transactivation, transactivation may account for the greatest level and most potent repression of inflammatory genes. Equally, NR3C1 transactivation is enhanced by β2-adrenoceptor agonists and may explain the enhanced clinical efficacy of β2-adrenoceptor/glucocorticoid combination therapies in asthma and chronic obstructive pulmonary disease. Finally, NR3C1 transactivation is reduced by inflammatory stimuli, including respiratory syncytial virus and human rhinovirus. This provides an explanation for glucocorticoid resistance. Continuing efforts to understand roles for glucocorticoid-dependent transactivation will provide opportunities to improve glucocorticoid therapies.
尽管糖皮质激素（皮质类固醇）是治疗慢性炎症性疾病最有效的抗炎药物，但其抑制炎症基因表达的机制仍未完全明确。糖皮质激素受体（NR3C1）与炎症转录因子直接相互作用以抑制转录活性，即反式抑制，是其作用机制之一。然而，NR3C1介导的转录激活，即反式激活，也是糖皮质激素作用的重要机制。糖皮质激素能迅速且显著地增加多种基因的表达，其中许多基因具有与抑制炎症基因表达相一致的特性。例如：双特异性磷酸酶DUSP1可降低丝裂原活化蛋白激酶的活性；糖皮质激素诱导的亮氨酸拉链蛋白（TSC22D3）可抑制核因子κB（NF-κB）和激活蛋白1（AP-1）的转录反应；κBα抑制剂（NFKBIA）可抑制NF-κB；锌指蛋白36（ZFP36）可使炎症mRNA不稳定并抑制其翻译；细胞周期调节因子CDKN1C可能减弱JUN N端激酶信号传导；G蛋白信号调节因子2（RGS2）通过减少Gαq偶联的G蛋白偶联受体（GPCRs）的信号传导，起到支气管保护作用。虽然糖皮质激素依赖性反式抑制可与反式激活同时存在，但反式激活可能是炎症基因最大程度和最有效抑制的原因。同样，β2肾上腺素能受体激动剂可增强NR3C1反式激活，这可能解释了β2肾上腺素能受体/糖皮质激素联合疗法在哮喘和慢性阻塞性肺疾病中临床疗效增强的原因。最后，包括呼吸道合胞病毒和人鼻病毒在内的炎症刺激可降低NR3C1反式激活。这为糖皮质激素抵抗提供了解释。持续努力了解糖皮质激素依赖性反式激活的作用，将为改善糖皮质激素治疗提供机会。
