4.6 Article

PDGF-D Expression Is Down-Regulated by TGFβ in Fibroblasts

Journal

PLOS ONE
Volume 9, Issue 10, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0108656

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Funding

  1. Fonds Speciaux de Recherche (UCL) - European Commission
  2. Fonds pour la recherche Scientifique en Rhumatologie
  3. Fonds Maurange

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Transforming growth factor-beta (TGF beta) is a key mediator of fibrogenesis. TGF beta is overexpressed and activated in fibrotic diseases, regulates fibroblast differentiation into myofibroblasts and induces extracellular matrix deposition. Platelet-derived growth factor (PDGF) is also a regulator of fibrogenesis. Some studies showed a link between TGF beta and PDGF in certain fibrotic diseases. TGF beta induces PDGF receptor alpha expression in scleroderma fibroblasts. PDGF-C and -D are the most recently discovered ligands and also play a role in fibrosis. In this study, we report the first link between TGF beta and PDGF-D and -C ligands. In normal fibroblasts, TGF beta down-regulated PDGF-D expression and up-regulated PDGF-C expression at the mRNA and protein levels. This phenomenon is not limited to TGF beta since other growth factors implicated in fibrosis, such as FGF, EGF and PDGF-B, also regulated PDGF-D and PDGF-C expression. Among different kinase inhibitors, only TGF beta receptor inhibitors and the I kappa B kinase (IKK) inhibitor BMS-345541 blocked the effect of TGF beta. However, activation of the classical NF-kappa B pathway was not involved. Interestingly, in a model of lung fibrosis induced by either bleomycin or silica, PDGF-D was down-regulated, which correlates with the production of TGF beta and other fibrotic growth factors. In conclusion, the down-regulation of PDGF-D by TGF beta and other growth factors may serve as a negative feedback in the network of cytokines that control fibrosis.

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