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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711861.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
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
Authors:Schwartze, J. T.; Becker, S.; Sakkas, E.; Wujak, L. A.; Niess, G.; Usemann, J.; Reichenberger, F.; Herold, S.; Vadasz, I.; Mayer, K.; Seeger, W.; Morty, R. E.
Date of Publication (YYYY-MM-DD):2014-02-07
Title of Journal:J Biol Chem
Volume:289
Issue / Number:6
Start Page:3262
End Page:3275
Audience:Not Specified
Abstract / Description:Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-beta is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-beta signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-beta signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-beta receptor Tgfbr3, also called betaglycan. Tgfbr3 was demonstrated to be a "switch" that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-beta to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung Tgfbr3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-beta signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.
Free Keywords:Activin Receptors, Type I/genetics/*metabolism; Animals; Endothelial Cells/cytology/metabolism; Female; Fibroblasts/cytology/*metabolism; Glucocorticoids/*pharmacology; Humans; Lung/cytology/*metabolism; Mice; Myocytes, Smooth Muscle/cytology/metabolism; NIH 3T3 Cells; Protein-Serine-Threonine Kinases/genetics/*metabolism; Proteoglycans/genetics/*metabolism; Receptors, Transforming Growth Factor beta/genetics/*metabolism; Signal Transduction/*drug effects/physiology; Smad1 Protein/genetics/*metabolism; Smad2 Protein/genetics/*metabolism; Smad3 Protein/genetics/*metabolism; Transforming Growth Factor beta/genetics/*metabolism; Fibroblast; Glucocorticoids; Lung; SMAD Transcription Factor; Transforming Growth Factor Beta (TGFbeta)
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%^ 1435822045
Identifiers:ISSN:1083-351X (Electronic) 0021-9258 (Linking) %R 10.1074/jbc.M113.541052
URL:http://www.ncbi.nlm.nih.gov/pubmed/24347165
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