Dirks N L, Li S, Huth B, Hochhaus G, Yates C R, Meibohm B
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Pharmazie. 2008 Dec;63(12):893-8.
The anti-inflammatory activity of inhaled glucocorticoids is primarily mediated through transrepression of pro-inflammatory transcription factors such as AP-1 and NF-kappaB, while systemic side effects are largely attributed to transactivation via glucocorticoid response elements (GRE) in the promoter region of responsive genes. The objective of this study is to investigate whether inhaled corticosteroids exhibit differences in their transactivation and transrepression potencies. A549 human alveolar epithelial type II like cells, stably transfected with a reporter plasmid containing an AP-1, NF-kappaB or GRE induced secreted alkaline phosphatase reporter gene (SEAP), were exposed to a panel of concentrations of the six inhaled and three systemic glucocorticoids. Glucocorticoid-induced changes in SEAP expression were quantified by chemiluminescence. For eight glucocorticoids (budesonide, desisobutyryl-cicle-sonide, dexamethasone, flunisolide, fluocortolone, fluticasone propionate, mometasone furoate, prednisolone) the EC50 for NF-kappaB mediated transrepression was significantly larger than that for both transactivation and transrepression via AP-1. For the remaining glucocorticoid (triamcinolone acetonide), it was greater than that for transactivation. It is concluded that, within the studied cell system, inhaled corticosteroids did not exhibit preferential transrepression, but had higher potencies for transactivation than for transrepression via NF-kappaB and had differential potencies for the two transrepression pathways.
吸入性糖皮质激素的抗炎活性主要通过对促炎转录因子如AP-1和NF-κB的反式抑制来介导，而全身副作用很大程度上归因于通过反应性基因启动子区域的糖皮质激素反应元件（GRE）进行的反式激活。本研究的目的是调查吸入性糖皮质激素在反式激活和反式抑制效力方面是否存在差异。将稳定转染含有AP-1、NF-κB或GRE诱导的分泌性碱性磷酸酶报告基因（SEAP）的报告质粒的A549人II型肺泡上皮样细胞暴露于一系列浓度的六种吸入性和三种全身性糖皮质激素中。通过化学发光法定量糖皮质激素诱导的SEAP表达变化。对于八种糖皮质激素（布地奈德、去异丁酰环索奈德、地塞米松、氟尼缩松、氟可龙、丙酸氟替卡松、糠酸莫米松、泼尼松龙），NF-κB介导的反式抑制的EC50显著大于通过AP-1进行的反式激活和反式抑制的EC50。对于其余的糖皮质激素（曲安奈德），它大于反式激活的EC50。得出的结论是，在所研究的细胞系统中，吸入性糖皮质激素没有表现出优先的反式抑制作用，但通过NF-κB进行反式激活的效力高于反式抑制，并且在两种反式抑制途径中具有不同的效力。
