黏蛋白 4 可削弱慢性鼻-鼻窦炎伴鼻息肉患者中皮质类固醇的抗炎作用。
MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps.
机构信息
Department of Pharmacy, University Hospital Consortium, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, Jaume I University, Castellon, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain.
Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain.
出版信息
J Allergy Clin Immunol. 2017 Mar;139(3):855-862.e13. doi: 10.1016/j.jaci.2016.06.064. Epub 2016 Sep 14.
BACKGROUND
Current evidence suggests that membrane-tethered mucins could mediate corticosteroid efficacy, interacting with glucocorticoid receptor (GR) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Mucin 4 (MUC4)-tethered mucin is expressed in nasal polyp (NP) epithelial cells and upregulated under inflammatory conditions. Moreover, MUC4β has the capacity to interact with other intracellular proteins. We hypothesized that MUC4 modulates corticosteroid efficacy of patients with CRSwNP.
OBJECTIVE
We sought to analyze the role of MUC4 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved.
METHODS
Eighty-one patients with CRSwNP took oral corticosteroids for 15 days. Corticosteroid resistance was evaluated by using nasal endoscopy. Expression of MUC4 and MUC4β was evaluated by means of real-time PCR, Western blotting, and immunohistochemistry. BEAS-2B knockdown with RNA interference for MUC4 (small interfering RNA [siRNA]-MUC4) was used to analyze the role of MUC4 in the anti-inflammatory effects of dexamethasone.
RESULTS
Twenty-two patients had NPs resistant to oral corticosteroids. MUC4 expression was upregulated in these patients. In siRNA-MUC4 BEAS-2B airway epithelial cells dexamethasone produced higher anti-inflammatory effects, increased inhibition of phospho-extracellular signal-regulated kinase 1/2, increased mitogen-activated protein kinase phosphatase 1 expression, and increased glucocorticoid response element activation. Immunoprecipitation and immunofluorescence experiments revealed that MUC4β forms a complex with GRα in the nuclei of NP epithelial cells from corticosteroid-resistant patients.
CONCLUSION
MUC4β participates in the corticosteroid resistance process, inhibiting normal GRα nuclear function. The high expression of MUC4 in patients with CRSwNP might participate in corticosteroid resistance.
背景
目前的证据表明，膜结合粘蛋白可能通过与慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）患者的糖皮质激素受体（GR）相互作用来介导皮质类固醇的疗效。粘蛋白 4（MUC4）-结合粘蛋白在鼻息肉（NP）上皮细胞中表达，并在炎症条件下上调。此外，MUC4β 具有与其他细胞内蛋白相互作用的能力。我们假设 MUC4 调节 CRSwNP 患者皮质类固醇的疗效。
目的
我们旨在分析 MUC4 在不同 CRSwNP 患者皮质类固醇疗效中的作用，并阐明所涉及的可能机制。
方法
81 例 CRSwNP 患者接受口服皮质类固醇治疗 15 天。通过鼻内镜评估皮质类固醇的耐药性。通过实时 PCR、Western blot 和免疫组织化学评估 MUC4 和 MUC4β 的表达。使用 RNA 干扰（siRNA）沉默 BEAS-2B 中的 MUC4（siRNA-MUC4）以分析 MUC4 在地塞米松抗炎作用中的作用。
结果
22 例患者的 NP 对口服皮质类固醇耐药。这些患者的 MUC4 表达上调。在 siRNA-MUC4 BEAS-2B 气道上皮细胞中，地塞米松产生了更高的抗炎作用，增加了磷酸化细胞外信号调节激酶 1/2 的抑制，增加了丝裂原活化蛋白激酶磷酸酶 1 的表达，并增加了糖皮质激素反应元件的激活。免疫沉淀和免疫荧光实验表明，MUC4β 在糖皮质激素耐药患者的 NP 上皮细胞核中与 GRα 形成复合物。
结论
MUC4β 参与皮质类固醇耐药过程，抑制正常的 GRα 核功能。CRSwNP 患者中 MUC4 的高表达可能参与皮质类固醇耐药。
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