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Título: | Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
Autor: | Alonso-Merino, Elvira CSIC; Martin-Orozco, Rosa CSIC; Ruiz-Llorente, Lidia CSIC ORCID; Martínez-Iglesias, Olaia CSIC; Velasco-Martín, Juan P.; Montero-Pedrazuela, Ana CSIC ORCID ; Fanjul, Luisa F.; Contreras-Jurado, Constanza CSIC ORCID; Regadera, Javier; Aranda, Ana CSIC ORCID | Palabras clave: | Thyroid hormone receptors TGF-β SMADs Fibrosis |
Fecha de publicación: | 31-may-2016 | Editor: | National Academy of Sciences (U.S.) | Citación: | Proceedings of the National Academy of Sciences of the United States of America 113: E3451-E3460 (2016) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.1073/pnas.1506113113 | URI: | http://hdl.handle.net/10261/267617 | DOI: | 10.1073/pnas.1506113113 | Identificadores: | doi: 10.1073/pnas.1506113113 e-issn: 1091-6490 issn: 0027-8424 |
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