Alteration of transforming growth factor-beta1 response involves down-regulation of Smad3 signaling in myofibroblasts from skin fibrosis.
Fibrosis is an unregulated tissue repair process whose predominant characteristics are the proliferation of myofibroblasts and an excessive deposition of extracellular matrix. Transforming growth factor (TGF)-beta1 is considered as one of the most fibrogenic cytokines. However, the molecular mechanisms involved in its profibrotic role are not fully understood. Here, we addressed the role of TGF-beta1 on cell proliferation and intracellular signal transduction in a pig model of skin fibrosis induced by gamma-irradiation. Primary myofibroblasts were isolated from the fibrotic tissue and their response to TGF-beta1 was compared to that of normal skin fibroblasts. The present results show that the differentiation of myofibroblasts involves a lack of TGF-beta1 growth inhibition and an impaired TGF-beta1 signaling. Receptor activity and Smad2/4 or Smad3/4 complex formation were similar in both cell types after TGF-beta1 treatment. However, the translocation of Smad3 protein into the nucleus was reduced in myofibroblasts as compared to that in fibroblasts, as well as its binding to target DNA sequences and the activation of the Smad binding elements found in the PAI-1. Interestingly, Smad2 was translocated similarly to the nucleus in both cell types suggesting that this protein may function normally in myofibroblasts. We propose that uncoupling of antiproliferative and profibrotic actions of TGF-beta1 in fibrosis may occur through differential regulation of the activities of Smad2 and Smad3 transcription factors.
Reisdorf
P
P
Laboratoire de Radiobiologie et d'Etude du Génome, Départment de Radiobiologie et Radiopathologie, Direction des Sciences du Vivant, Commisariat à l'Energie Atomique, Saclay, Gif sur Yvette, France.
Lawrence
D A
DA
Sivan
V
V
Klising
E
E
Martin
M T
MT
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005355:Fibrosis; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000473:pathology* / Q000503:physiopathology*; D051900:Smad3 Protein; D013552:Swine; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1