Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3451-60. doi: 10.1073/pnas.1506113113. Epub 2016 May 31.


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 SMAD-binding 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.

Keywords: SMADs; TGF-β; fibrosis; thyroid hormone receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / adverse effects
  • Bleomycin / pharmacology
  • Carbon Tetrachloride Poisoning / genetics
  • Carbon Tetrachloride Poisoning / metabolism
  • Carbon Tetrachloride Poisoning / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Knockout
  • Signal Transduction*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Triiodothyronine / genetics
  • Triiodothyronine / metabolism*


  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Transforming Growth Factor beta
  • Triiodothyronine
  • Bleomycin