Increased glucocorticoid receptor β alters steroid response in glucocorticoid-insensitive asthma
Increased glucocorticoid receptor β alters steroid response in glucocorticoid-insensitive asthma
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DOI：
10.1164/rccm.200507-1046oc
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发表时间：
2006-03-15
影响因子：
24.7
通讯作者：
Leung, DYM
中科院分区：
文献类型：
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作者：
Goleva, E;Li, LB;Leung, DYM
理由：糖皮质激素（GC）在治疗哮喘方面非常有效。目的：探讨哮喘患者支气管肺泡灌洗（BAL）细胞对激素的功能反应。以及，试图定义糖皮质激素受体（GCR）β（剪接变异体，显性负抑制剂，经典的GCR α）在控制GCR α核转位和transactivation在molecularlevel.Methods和测量：纤维支气管镜与收集的BAL液进行7例GC敏感性哮喘和8例GC不敏感性哮喘患者的功能作用。通过免疫荧光染色分析BAL细胞中GCR α细胞对10（-6）M地塞米松处理的响应穿梭和GCR β表达。GCR α functions.Main结果：显着减少GCR α在响应类固醇的核转位的GCR β mRNA的过表达和沉默的影响进行了评估发现在BAL细胞与GC不敏感的哮喘患者。来自GC不敏感性哮喘患者的BAL巨噬细胞的细胞质和细胞核GCR β水平显著增加。结果表明，GCR α核转位及其反式激活特性随GCR β基因向DO-11.10细胞系中的病毒转译水平而成比例地降低。GC不敏感性哮喘患者的人BAL巨噬细胞中GCR β mRNA的RNA沉默导致地塞米松诱导的GCR α transactivation.Conclusions：GC不敏感性与BAL细胞中GCR α核转位丢失和GCR β升高相关，这可能抑制GCR α对类固醇的反式激活。
Rationale: Glucocorticoids (GCs) are highly effective in the treatment of asthma. However, some individuals have GC-insensitive asthma.Objectives: To evaluate the functional response to steroids of bronchoalveolar lavage (BAL) cells from sites of airway inflammation from patients with GC-insensitive versus GC-sensitive asthma. As well, to attempt to define the functional role of glucocorticoid receptor (GCR)beta (a splicing variant, and dominant negative inhibitor of, the classic GCR alpha) in controlling GCR alpha nuclear translocation and transactivation at a molecular level.Methods and Measurements: Fiberoptic bronchoscopy with collection of BAL fluid was performed on seven patients with GC-sensitive asthma and eight patients with GC-insensitive asthma. GCR alpha cellular shuttling in response to 10(-6) M dexamethasone treatment and GCR beta expression were analyzed in BAL cells by immunofluorescence staining. The effects of overexpression and silencing of GCR beta mRNA on GCR alpha function were assessed.Main Results: Significantly reduced nuclear translocation of GCR alpha in response to steroids was found in BAL cells from patients with GC-insensitive asthma. BAL macrophages from patients with GC-insensitive asthma had significantly increased levels of cytoplasmic and nuclear GCR beta. It was demonstrated that GCR alpha nuclear translocation and its transactivation properties were proportionately reduced by level of viral transcluction of the GCR beta gene into the DO-11.10 cell line. RNA silencing of GCR beta mRNA in human BAL macrophages from patients with GC-insensitive asthma resulted in enhanced dexamethasone-induced GCR alpha transactivation.Conclusions: GC insensitivity is associated with loss of GCR alpha nuclear translocation in BAL cells and elevated GCR beta, which may inhibit GCR alpha transactivation in response to steroids.