ABSTRACT
Transforming growth factor-ß (TGFß) is a key mediator of fibrogenesis. TGFß 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 TGFß and PDGF in certain fibrotic diseases. TGFß 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 TGFß and PDGF-D and -C ligands. In normal fibroblasts, TGFß down-regulated PDGF-D expression and up-regulated PDGF-C expression at the mRNA and protein levels. This phenomenon is not limited to TGFß 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 TGFß receptor inhibitors and the IκB kinase (IKK) inhibitor BMS-345541 blocked the effect of TGFß. However, activation of the classical NF-κB 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 TGFß and other fibrotic growth factors. In conclusion, the down-regulation of PDGF-D by TGFß and other growth factors may serve as a negative feedback in the network of cytokines that control fibrosis.
