Laboratory of Allergology and Pulmonary Diseases Dept of Pathology and Medical Biology GRIAC Research Institute University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
Eur Respir J. 2012 Feb;39(2):439-45. doi: 10.1183/09031936.00017911. Epub 2011 Aug 4.
A subset of asthma patients suffer from glucocorticoid (GC) insensitivity. T-helper cell type 17 cells have an emerging role in GC insensitivity, although the mechanisms are still poorly understood. We investigated whether interleukin (IL)-17A induces GC insensitivity in airway epithelium by studying its effects on responsiveness of tumour necrosis factor (TNF)-α-induced IL-8 production to budesonide in human bronchial epithelial 16HBE cells. We unravelled the underlying mechanism by the use of specific pathway inhibitors, reporter and overexpression constructs and a histone deacetylase (HDAC) activity assay. We demonstrated that IL-17A-induced IL-8 production is normally sensitive to GCs, while IL-17A pre-treatment significantly reduced the sensitivity of TNF-α-induced IL-8 production to budesonide. IL-17A activated the p38, extracellular signal-related kinase (ERK) and phosphoinositide-3-kinase (PI3K) pathways, and the latter appeared to be involved in IL-17A-induced GC insensitivity. Furthermore, IL-17A reduced HDAC activity, and overexpression of HDAC2 reversed IL-17A-induced GC insensitivity. In contrast, IL-17A did not affect budesonide-induced transcriptional activity of the GC receptor, suggesting that IL-17A does not impair the actions of the ligated GC receptor. In conclusion, we have shown for the first time that IL-17A induces GC insensitivity in airway epithelium, which is probably mediated by PI3K activation and subsequent reduction of HDAC2 activity. Thus, blockade of IL-17A or downstream signalling molecule PI3K may offer new strategies for therapeutic intervention in GC-insensitive asthma.
哮喘患者中有一部分存在糖皮质激素（GC）不敏感。辅助性 T 细胞 17 型（Th17 细胞）在 GC 不敏感中具有重要作用，但其机制尚不清楚。本研究通过研究白细胞介素（IL）-17A 对肿瘤坏死因子（TNF）-α诱导的 IL-8 产生对布地奈德反应性的影响，探讨其在气道上皮细胞 GC 不敏感中的作用。我们使用特定的通路抑制剂、报告基因和过表达构建体以及组蛋白去乙酰化酶（HDAC）活性测定法，揭示了潜在的机制。我们证明了 IL-17A 诱导的 IL-8 产生通常对 GC 敏感，而 IL-17A 预处理可显著降低 TNF-α诱导的 IL-8 产生对布地奈德的敏感性。IL-17A 激活了 p38、细胞外信号调节激酶（ERK）和磷酸肌醇 3-激酶（PI3K）通路，后者似乎参与了 IL-17A 诱导的 GC 不敏感。此外，IL-17A 降低了 HDAC 活性，HDAC2 的过表达逆转了 IL-17A 诱导的 GC 不敏感。相反，IL-17A 不影响布地奈德诱导的 GC 受体的转录活性，这表明 IL-17A 不会损害结合 GC 受体的作用。总之，我们首次证明 IL-17A 可诱导气道上皮细胞中的 GC 不敏感，这可能是通过 PI3K 激活和随后降低 HDAC2 活性介导的。因此，阻断 IL-17A 或下游信号分子 PI3K 可能为 GC 不敏感型哮喘的治疗干预提供新策略。
