Alteration of Transforming Growth Factor-β1 Response Involves Down-Regulation of Smad3 Signaling in Myofibroblasts from Skin Fibrosis

摘要

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)-β1 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-β1 on cell proliferation and intracellular signal transduction in a pig model of skin fibrosis induced by γ-irradiation. Primary myofibroblasts were isolated from the fibrotic tissue and their response to TGF-β1 was compared to that of normal skin fibroblasts. The present results show that the differentiation of myofibroblasts involves a lack of TGF-β1 growth inhibition and an impaired TGF-β1 signaling. Receptor activity and Smad2/4 or Smad3/4 complex formation were similar in both cell types after TGF-β1 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-β1 in fibrosis may occur through differential regulation of the activities of Smad2 and Smad3 transcription factors.