Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses
Entidad
UAM. Departamento de Anatomía, Histología y Neurociencia; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)Editor
National Academy of SciencesFecha de edición
2016-06-14Cita
10.1073/pnas.1506113113
Proceedings of the National Academy of Sciences of the United States of America 113.24 (2016): E3451–E3460
ISSN
0027-8424DOI
10.1073/pnas.1506113113Financiado por
This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER fundsProyecto
Gobierno de España. BFU2011-28058; Gobierno de España. BFU2014-53610P; Comunidad de Madrid. S2011/BMD-2328/TIRONETVersión del editor
http://dx.doi.org/10.1073/pnas.1506113113Materias
Fibrosis; SMADs; TGF-β; Thyroid hormone receptors; MedicinaResumen
TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.
Lista de ficheros
Google Scholar:Alonso-Merino, Elvira
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Orozco, Rosa Martín
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Ruíz-Llorente, Lidia
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Martínez-Iglesias, Olaia A.
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Velasco-Martín, Juan Pedro
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Montero-Pedrazuela, Ana
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Fanjul-Rodríguez, Luisa
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Contreras-Jurado, Constanza
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Regadera, Javier
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Aranda, Ana
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