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RESEARCH PRODUCT

MUC1-CT mediates corticosteroid responses in COPD

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Background: Corticosteroid resistance is an acquired condition in chronic obstructive pulmonary disease (COPD) patients and a challenge to develop new anti-inflammatory therapies. In previous reports we showed that cytoplasmic tail of the membrain tethered mucin 1 (MUC1-CT) interacts with glucocorticoid receptor (GR) mediating corticosteroid anti-inflammatory efficacy. Objectives: To analyze the role of MUC1-CT as a key marker of corticosteroid efficacy in COPD Methods: The expression of MUC1-CT and the anti-inflammatory role of dexamethasone were evaluated in neutrophils and bronchial epithelial cells from healthy and COPD patients. Anti-inflammatory effects of dexamethasone and glucocorticoid response element (GRE) activation were tested in bronchial epithelial cells silenced for MUC1 (siRNA-MUC1). Anti-inflammatory effects of dexamethasone were analyzed in a KO-MUC1 model of seven-day smoking mouse. Results: MUC1-CT was down-regulated in lung tissue, neutrophils and airway epithelial cells from COPD patients. Cigarette smoke extract down-regulated MUC1-CT expression and impaired dexamethasone anti-inflammatory effects. In siRNA-MUC1 cells, dexamethasone decreased its anti-inflammatory properties, and showed a lesser activation of GRE signal and induction of anti-inflammatory genes. Confocal fluorescence microscope analysis and immunoprecipitation experiments showed colocalization and interaction of MUC1-CT and GR in response to dexamethasone that decreased in presence of cigarette smoke. In KO-MUC1 smoker mouse model dexamethasone showed poor anti-inflammatory effects. Conclusions: MUC1-CT mediates the anti-inflammatory properties of corticosteroids and the lack of its expression in COPD increases resistance to corticosteroids.