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MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease.

Respiratory research (2018-11-22)
Javier Milara, Lucía Díaz-Platas, Sonia Contreras, Pilar Ribera, Inés Roger, Beatriz Ballester, Paula Montero, Ángel Cogolludo, Esteban Morcillo, Julio Cortijo

Lung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models. MUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3α were measured by ELISA. The effect of MUC1 on inflammation and corticosteroid anti-inflammatory effects was measured using cell siRNA in vitro and Muc1-KO in vivo animal models. MUC1-CT expression was downregulated in lung tissue, bronchial epithelial cells and lung neutrophils from smokers (n = 11) and COPD (n = 11) patients compared with healthy subjects (n = 10). MUC1 was correlated with FEV1% (ρ = 0.7479; p < 0.0001) in smokers and COPD patients. Cigarette smoke extract (CSE) decreased the expression of MUC1 and induced corticosteroid resistance in human primary bronchial epithelial cells and human neutrophils. MUC1 Gene silencing using siRNA-MUC1 impaired the anti-inflammatory effects of dexamethasone and reduced glucocorticoid response element activation. Dexamethasone promoted glucocorticoid receptor alpha (GRα) and MUC1-CT nuclear translocation and co-localization that was inhibited by CSE. Lung function decline and inflammation induced by lipopolysaccharide and cigarette smoke in Muc1 KO mice was resistant to dexamethasone. These results confirm a role for MUC1-CT mediating corticosteroid efficacy in COPD.

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Anti-MAP Kinase, Activated (Diphosphorylated ERK-1&2) antibody, Mouse monoclonal, clone MAPK-YT, purified from hybridoma cell culture
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture