Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-beta signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts
Glucocorticoids are regarded as the main therapeutic option for many pulmonary diseases, performing outstandingly well in asthmatic patients, however, failing to benefit patients suffering from the acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and impaired lung development associated with bronchopulmonary dysplasia (BPD), often seen in pre-term infants. The transforming growth factor (TGF)-beta polypeptide has been implicated as a pathogenic mediator of all of these pulmonary pathologies, which prompted us to investigate the crosstalk between glucocorticoid and TGF-beta signaling. The glucocorticoid dexamethasone potentiated the TGF-beta Acvrl1/Smad1/5/8 signaling axis, and inhibited the TGF-beta Tgfbr1/Smad2/3 signaling axis in NIH/3T3 fibroblast-like mouse cells, in smooth muscle cells, primary lung fibroblasts, and endothelial cells. The accessory type III TGF-beta receptor (Tgfbr3), which is also called betaglycan, was increased by dexamethasone. Betaglycan acted as a redirecting switch which increased Acvrl1/Smad1 and inhibited Tgfbr1/Smad2/3 signaling in lung fibroblasts. Dexamethasone activated Acvrl1/Smad1 signaling in several constituent pulmonary cell types. Furthermore, this study demonstrated that this axis was active in lung fibroblasts, and also inhibited Tgfbr1/Smad2/3 signaling. Fibroblast-to-myofibroblast differentiation of primary lung fibroblasts synergistically increased during treatment with dexamethasone and TGF-beta. This was evident by an accumulation of smooth muscle myosin and smooth muscle actin. Previous studies have demonstrated that myofibroblast differentiation is exclusively Smad1-dependent. Intraperitoneal application of dexamethasone to live C57BL/6J mice resulted in increased in vivo pulmonary Tgfbr3 expression and phospho-Smad1 levels. Interestingly, this effect was lung-specific. Overall, in this study we demonstrate that glucocorticoids impact TGF-beta signaling in pulmonary cell types as well as in vivo in mice lungs. This may be relevant for normal lung physiology and pulmonary pathology.
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