Abstract
Transforming growth factor-β (TGFβ) is a key mediator of fibrogenesis. TGFβ 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 TGFβ and PDGF in certain fibrotic diseases. TGFβ 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 TGFβ and PDGF-D and -C ligands. In normal fibroblasts, TGFβ down-regulated PDGF-D expression and up-regulated PDGF-C expression at the mRNA and protein levels. This phenomenon is not limited to TGFβ 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 TGFβ receptor inhibitors and the IκB kinase (IKK) inhibitor BMS-345541 blocked the effect of TGFβ. 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 TGFβ and other fibrotic growth factors. In conclusion, the down-regulation of PDGF-D by TGFβ and other growth factors may serve as a negative feedback in the network of cytokines that control fibrosis.
Highlights
Transforming growth factor-b (TGFb) family members are cytokines that regulate numerous physiological processes such as embryonic development, cell differentiation, proliferation, migration and extracellular matrix production [1,2]
In this study we have shown that TGFb regulates Platelet-derived growth factor (PDGF)-C and -D ligand expression at both the mRNA and the protein level in normal human fibroblasts
This is the first study showing that the expression of PDGF-C and -D ligands is regulated by TGFb
Summary
Transforming growth factor-b (TGFb) family members are cytokines that regulate numerous physiological processes such as embryonic development, cell differentiation, proliferation, migration and extracellular matrix production [1,2]. Smad proteins are the core components of the intracellular signaling cascade of TGFb receptors. The Smad proteins transduce signals from the cell surface directly to the nucleus where they regulate gene transcription in cooperation with co-activators and/or corepressors. In addition to the Smad pathway, known as the conventional pathway, Smad-independent pathways can be activated by TGFb, including TGFb-associated kinase 1 (TAK1) [8], certain MAPKs such as extracellular signal-regulated kinase (ERK) 1 and 2, Jun N-terminal kinase (JNK) and p38 mitogenactivated protein kinase [8,9]. The PI3K-Akt-mTOR pathway has been reported to be activated by TGFb [10]. The importance of these alternative pathways, NF-kB in particular, has been debated. NF-kB activation by TGFb seems to be cell type dependent [11,12]
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