RT Journal Article
SR Electronic
T1 Role of MUC1 in idiopathic pulmonary fibrosis: mechanistic insights
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA4889
DO 10.1183/1393003.congress-2017.PA4889
VO 50
IS suppl 61
A1 Beatriz Ballester
A1 Ines Roger
A1 Sonia Contreras
A1 Paula Montero
A1 Javier Milara
YR 2017
UL http://erj.ersjournals.com/content/50/suppl_61/PA4889.abstract
AB Background:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible form of fibrotic interstitial lung disease. MUC1, a membrane-bound O-glycoprotein, is considered as oncogenic molecule by altering signaling pathways involved in cellular processes related to IPF. In previous studies we have observed an up-regulation of MUC1 and its phosphorylated forms in IPF lung tissue. However the exact participation of MUC1 in IPF is currently unknown.Objective: To analyze the mechanism of MUC1-induced lung fibrosis in different cellular and animal models of IPF.Methods: The intracellular mechanism of MUC1 was evaluated by western blot, immunoprecipation and immunofluorescence in alveolar type II A549 and fibroblast MRC5, and IPF primary alveolar type II epithelial cells and lung fibroblasts. Cells were stimulated with TGFβ1. Lung tissue from human healthy/IPF and bleomycin-induced IPF mice wild type/ knockout MUC1 (KO-MUC1) was analyzed to explore MUC1 intracellular interactions by immunofluorescence.Results: Western blot indicated that TGFβ1 activated β-catenin and p-Smad2/3, which phosphorylated and activated MUC1 cytoplasmic tail (CT) at 1224 and 1229 treonin and tirosin residues. Immunoprecipitation and immunofluorescence studies showed that the multi-protein complex among pSmad2/3, β-catenin and MUC1-CT migrated into the nucleus to activate fibrotic genes in human cells and human and animal lung tissue. Unlike wild type mice, KO-MUC1 mice were protected against IPF, improving lung function, survival and fibrotic lung tissue remodeling.Conclusions: MUC1-CT collaborates with TGFβ1 to induce IPF progression. Therefore, pharmacologic targeting of MUC1-CT may be a promising option for the treatment of IPF.