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From the 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
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)-ß1 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-ß1 on cell proliferation and intracellular signal
transduction in a pig model of skin fibrosis induced by
-irradiation. Primary myofibroblasts were isolated from the fibrotic
tissue and their response to TGF-ß1 was compared to that of normal
skin fibroblasts. The present results show that the differentiation of
myofibroblasts involves a lack of TGF-ß1 growth inhibition and an
impaired TGF-ß1 signaling. Receptor activity and Smad2/4 or Smad3/4
complex formation were similar in both cell types after TGF-ß1
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-ß1 in
fibrosis may occur through differential regulation of the activities of
Smad2 and Smad3 transcription factors.
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