An analysis of glucocorticoid receptor-mediated gene expression in BEAS-2B human airway epithelial cells identifies distinct, ligand-directed, transcription profiles with implications for asthma therapeutics
An analysis of glucocorticoid receptor-mediated gene expression in BEAS-2B human airway epithelial cells identifies distinct, ligand-directed, transcription profiles with implications for asthma therapeutics
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DOI：
10.1111/bph.13014
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发表时间：
2015-03-01
影响因子：
7.3
通讯作者：
Giembycz, M.
中科院分区：
文献类型：
--
作者：
Joshi, T.;Johnson, M.;Giembycz, M.
背景和目的国际哮喘指南推荐吸入性糖皮质激素作为单药治疗用于所有轻中度哮喘患者，因为它们能够抑制气道炎症。目前的证据表明，糖皮质激素的治疗益处是由于抗炎和促炎基因的反式激活和反式阻遏。然而，在这方面，临床相关的糖皮质激素在调节基因表达的能力方面的等效程度尚不清楚。实验方法使用糖皮质激素反应元件荧光素酶报告基因结合糖皮质激素诱导的编码具有抗炎和不良反应的蛋白质的基因的分析，对BEAS-2B人气道上皮细胞中糖皮质激素受体（GR）介导的基因反式激活进行药效学研究。关键结果使用反式激活作为功能相关的输出，给定的糖皮质激素显示出独特的基因表达指纹，其中内在功效和GR密度是重要的决定因素。我们表明，根据选择用于分析的基因，给定的糖皮质激素可以表现为拮抗剂、部分激动剂、完全激动剂甚至超级激动剂。在可能的情况下，不同的，组织依赖性的基因表达谱在体内复制，那么抗炎和不良反应的潜力，目前可作为哮喘治疗的许多糖皮质激素可能不是equivalent.Conclusions and ImplicationsThe基因表达指纹的产生在目标和脱靶人体组织可以帮助GR激动剂的合理设计，提高治疗比例。这种方法可以识别出用于管理严重哮喘和其他炎症性疾病的化合物，其中全身暴露是可取的。
Background and PurposeInternational asthma guidelines recommend that inhaled glucocorticoids be used as a monotherapy in all patients with mild to moderate disease because of their ability to suppress airways inflammation. Current evidence suggests that the therapeutic benefit of glucocorticoids is due to the transactivation and transrepression of anti-inflammatory and pro-inflammatory genes respectively. However, the extent to which clinically relevant glucocorticoids are equivalent in their ability to modulate gene expression is unclear.Experimental ApproachA pharmacodynamics investigation of glucocorticoid receptor (GR)-mediated gene transactivation in BEAS-2B human airway epithelial cells was performed using a glucocorticoid response element luciferase reporter coupled with an analysis of glucocorticoid-inducible genes encoding proteins with anti-inflammatory and adverse-effect potential.Key ResultsUsing transactivation as a functionally relevant output, a given glucocorticoid displayed a unique, gene expression fingerprint' where intrinsic efficacy and GR density were essential determinants. We showed that depending on the gene selected for analysis, a given glucocorticoid can behave as an antagonist, partial agonist, full agonist or even super agonist'. In the likely event that different, tissue-dependent gene expression profiles are reproduced in vivo, then the anti-inflammatory and adverse-effect potential of many glucocorticoids currently available as asthma therapeutics may not be equivalent.Conclusions and ImplicationsThe generation of gene expression fingerprints' in target and off-target human tissues could assist the rational design of GR agonists with improved therapeutic ratios. This approach could identify compounds that are useful in the management of severe asthma and other inflammatory disorders where systemic exposure is desirable.