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

ABSTRACT: 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-?1) 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-?1-induced signaling mechanisms and identified novel pathways impacted by estrogen in bronchial epithelial cells. METHODS:We investigated a role for E2 in modulating TGF-?1-induced epithelial to mesenchymal transition (EMT) in bronchial epithelial cells (BEAS-2Bs) and characterized the effect of TGF-?1 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-?1-induced EMT; however, we report the novel observation that TGF-?1 repressed ESR expression, most notably estrogen receptor alpha (ESR1). Results of the RNA-Seq analysis showed that TGF-?1 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-?1. 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.

SUBMITTER: Smith LC

PROVIDER: S-EPMC6117929 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Smith L Cody LC Moreno Santiago S Robertson Lauren L Robinson Sarah S Gant Kristal K Bryant Andrew J AJ Sabo-Attwood Tara T

Respiratory research 20180830 1

<h4>Background</h4>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 investig ...[more]

PMID: 30165855

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Project description:BACKGROUND:TGF-beta is a multifunctional growth factor involved in regulating a variety of cellular activities. Unlike mammals, the function of TGF-beta in the reproduction of lower vertebrates, such as fish, is not clear. Recently, we showed that TGF-beta1 inhibits gonadotropin- and 17alpha, 20beta-dihydroxyprogesterone (DHP)-induced maturation in zebrafish. The aim of the present study was to investigate the mechanisms underlying this action. METHOD:To determine if the effect of TGF-beta1 on oocyte maturation involves transcription and/or translation, ovarian follicles were pre-treated with actinomycin D, a blocker of transcription, and cyclohexamide, an inhibitor of translation, and incubated with hCG or DHP, either alone or in combination with TGF-beta1 and oocyte maturation scored. To determine the effect of TGF-beta1 on mRNA levels of several key effectors of oocyte maturation, three sets of experiments were performed. First, follicles were treated with control medium or TGF-beta1 for 2, 6, 12, and 24 h. Second, follicles were treated with different concentrations of TGF-beta1 (0 to 10 ng/ml) for 18 h. Third, follicles were incubated with hCG in the absence or presence of TGF-beta1 for 18 h. At the end of each experiment, total RNA was extracted and reverse transcribed. PCR using primers specific for 20beta-hydroxysteroid dehydrogenase (20beta-HSD) which is involved in DHP production, follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), the two forms of membrane progestin receptor: mPR-alpha and mPR-beta, as well as GAPDH (control), were performed. RESULTS:Treatment with actinomycin D, a blocker of transcription, reduced the inhibitory effect of TGF-beta1 on DHP-induced oocyte maturation, indicating that the inhibitory action of TGF-beta1 is in part due to regulation of gene transcription. Treatment with TGF-beta1 caused a dose and time-dependent decrease in mRNA levels of 20beta-HSD, LHR and mPR-beta in follicles. On the other hand, TGF-beta1 had no effect on mPR-alpha mRNA expression and increased FSHR mRNA levels. Furthermore, hCG upregulated 20beta-HSD, LHR and mPR-beta mRNA levels, but this stimulatory effect was blocked by TGF-beta1. CONCLUSION:These findings suggest that TGF-beta1 acts at multiple sites, including LHR, 20beta-HSD and mPR-beta, to inhibit zebrafish oocyte maturation.

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

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

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