Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells

Respir Res. 2018 Aug 30;19(1):160. doi: 10.1186/s12931-018-0861-5.


Background: Sex differences in idiopathic pulmonary fibrosis (IPF) suggest a protective role for estrogen (E2); however, mechanistic studies in animal models have produced mixed results. Reports using cell lines have investigated molecular interactions between transforming growth factor beta1 (TGF-β1) and estrogen receptor (ESR) pathways in breast, prostate, and skin cells, but no such interactions have been described in human lung cells. To address this gap in the literature, we investigated a role for E2 in modulating TGF-β1-induced signaling mechanisms and identified novel pathways impacted by estrogen in bronchial epithelial cells.

Methods: We investigated a role for E2 in modulating TGF-β1-induced epithelial to mesenchymal transition (EMT) in bronchial epithelial cells (BEAS-2Bs) and characterized the effect of TGF-β1 on ESR mRNA and protein expression in BEAS-2Bs. We also quantified mRNA expression of ESRs in lung tissue from individuals with IPF and identified potential downstream targets of E2 signaling in BEAS-2Bs using RNA-Seq and gene set enrichment analysis.

Results: E2 negligibly modulated TGF-β1-induced EMT; however, we report the novel observation that TGF-β1 repressed ESR expression, most notably estrogen receptor alpha (ESR1). Results of the RNA-Seq analysis showed that TGF-β1 and E2 inversely modulated the expression of several genes involved in processes such as extracellular matrix (ECM) turnover, airway smooth muscle cell contraction, and calcium flux regulation. We also report that E2 specifically modulated the expression of genes involved in chromatin remodeling pathways and that this regulation was absent in the presence of TGF-β1.

Conclusions: Collectively, these results suggest that E2 influences unexplored pathways that may be relevant to pulmonary disease and highlights potential roles for E2 in the lung that may contribute to sex-specific differences.

Keywords: Estrogen; Estrogen receptor; Fibrosis; Lung; Transforming growth factor beta1.

MeSH terms

  • Aged
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Estrogens / pharmacology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Receptors, Estrogen / biosynthesis*
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / metabolism*
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Transforming Growth Factor beta1 / pharmacology*


  • Estrogens
  • Receptors, Estrogen
  • Transforming Growth Factor beta1