MUC4 is overexpressed in idiopathic pulmonary fibrosis and collaborates with transforming growth factor β inducing fibrotic responses.
Javier MilaraBeatriz BallesterM J SafontEnrique ArtiguesJuan EscriváEsteban MorcilloJulio CortijoPublished in: Mucosal immunology (2020)
Several mucins are implicated in idiopathic pulmonary fibrosis (IPF); however, there is no evidence regarding the role of MUC4 in the development of IPF. Here we demonstrated that MUC4 was overexpressed in IPF patients (n = 22) compared with healthy subjects (n = 21) and located in pulmonary arteries, bronchial epithelial cells, fibroblasts, and hyperplastic alveolar type II cells. Decreased expression of MUC4 using siRNA-MUC4 inhibited the mesenchymal/myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as cell senescence and fibroblast proliferation induced by TGF-β1. The induction of the overexpression of MUC4 increased the effects of TGF-β1 on mesenchymal/myofibroblast transformations and cell senescence. MUC4 overexpression and siRNA-MUC4 gene silencing increased or decreased, respectively, the phosphorylation of TGFβRI and SMAD3, contributing to smad-binding element activation. Immunoprecipitation analysis and confocal immunofluorescence showed the formation of a protein complex between MUC4β/p-TGFβRI and p-SMAD3 in the cell membrane after TGF-β1 stimulation and in lung tissue from IPF patients. Bleomycin-induced lung fibrosis was reduced in mice transiently transfected with siRNA-MUC4. This study shows that MUC4 expression is enhanced in IPF and promotes fibrotic processes in collaboration with TGF-β1 canonical pathway that could be an attractive druggable target for human IPF.
Keyphrases
- idiopathic pulmonary fibrosis
- transforming growth factor
- epithelial mesenchymal transition
- interstitial lung disease
- end stage renal disease
- endothelial cells
- stem cells
- poor prognosis
- induced apoptosis
- newly diagnosed
- ejection fraction
- chronic kidney disease
- binding protein
- dna damage
- type diabetes
- bone marrow
- transcription factor
- cell proliferation
- cancer therapy
- adipose tissue
- peritoneal dialysis
- pulmonary hypertension
- cell therapy
- patient reported outcomes
- high glucose
- insulin resistance
- endoplasmic reticulum stress
- cell cycle arrest
- diabetic rats
- skeletal muscle
- cell death
- drug induced
- pluripotent stem cells
- liver fibrosis