Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps
Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps
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DOI：
10.1016/j.jaci.2014.07.011
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发表时间：
2015-02-01
影响因子：
14.2
通讯作者：
Cortijo, Julio
中科院分区：
文献类型：
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作者：
Milara, Javier;Peiro, Teresa;Cortijo, Julio
背景：许多慢性鼻-鼻窦炎合并鼻息肉(CRSwNP)患者对口服糖皮质激素有抵抗力。粘蛋白1(MUC1)具有抗炎作用，其胞浆尾部(CT)与转录因子相互作用，促进转录因子的核转位。由于糖皮质激素受体(GR)核转位是糖皮质激素抗炎作用的关键，我们假设MUC1参与了糖皮质激素的疗效。目的：分析MUC1在CRSwNP患者不同队列的糖皮质激素疗效中的作用，并阐明其可能的机制。通过鼻内窥镜评估皮质类固醇抵抗。用实时荧光定量聚合酶链式反应、Western blotting和免疫组织化学方法检测MUC1和MUC1CT的表达。结果：19例鼻息肉患者存在口服糖皮质激素耐药的鼻息肉(NP-CR)。在这些患者中，MUC1表达下调。NP-CR患者的原代上皮细胞对地塞米松的抗炎作用不敏感。在siRNA-MUC1BEAS-2B中，地塞米松表现出较弱的抗炎作用，对磷酸化细胞外信号调节蛋白激酶1/2的抑制减少，丝裂原活化蛋白激酶磷酸酶1的增加不那么严重，GR核转位减少。免疫沉淀实验表明，MUC1-CT和GRα形成蛋白质复合体，并在地塞米松作用下移位到细胞核。结论：MUC1-CT参与了介导GRα核转位的皮质类固醇激素反应。CRSwNP患者MUC1的低表达可能参与了糖皮质激素抵抗。
Background: A number of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) are resistant to oral corticosteroids. Mucin 1 (MUC1) shows anti-inflammatory properties, and its cytoplasmic tail (CT) interacts with transcription factors, facilitating their nuclear translocation. Because glucocorticoid receptor (GR) nuclear translocation is key to the anti-inflammatory effect of corticosteroids, we hypothesized that MUC1 is involved in the effectiveness of corticosteroids.Objective: To analyze the role of MUC1 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved.Methods: Seventy-three patients with CRSwNP took oral corticosteroids for 15 days. Corticosteroid resistance was evaluated by nasal endoscopy. The expression of MUC1 and MUC1 CT was evaluated by real-time PCR, Western blotting, and immunohistochemistry. Beas-2B knockdown with RNA interference for MUC1 (siRNA-MUC1) was used to analyze the role of MUC1 in the anti-inflammatory effects of dexamethasone.Results: Nineteen patients had nasal polyps that were resistant to oral corticosteroids (NP-CR). MUC1 expression was downregulated in these patients. Primary epithelial cells from patients with NP-CR were insensitive to the anti-inflammatory effects of dexamethasone. In siRNA-MUC1 Beas-2B, dexamethasone showed weaker anti-inflammatory effects, a reduced inhibition of phospho-extracellular-signal-regulated kinases 1/2, a less severe mitogen-activated protein kinase phosphatase 1 increase, and a reduced GR nuclear translocation. Immunoprecipitation experiments revealed that MUC1-CT and GR alpha form protein complexes and translocate to the nucleus in response to dexamethasone. MUC1-CT-GR alpha complex was downregulated in NP-CR tissue.Conclusion: MUC1-CT participates in the corticosteroid response that mediates GR alpha nuclear translocation. The low expression of MUC1 in patients with CRSwNP may participate in corticosteroid resistance.