FGF-1 reverts epithelial-mesenchymal transition induced by TGF-β1 through MAPK/ERK kinase pathway

Ramos C, Becerril C, Montano M, Garcia-De-Alba C, Ramirez R, Checa M, Pardo A, Selman M. FGF-1 reverts epithelial-mesenchymal transition induced by TGF-beta 1 through MAPK/ERK kinase pathway. Am J Physiol Lung Cell Mol Physiol 299: L222-L231, 2010. First published May 21, 2010; doi:10.1152/ajplung.00070.2010.-Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the expansion of the fibroblast/myofibroblast population and aberrant remodeling. However, the origin of mesenchymal cells in this disorder is still under debate. Recent evidence indicates that epithelial-mesenchymal transition (EMT) induced primarily by TGF-beta 1 plays an important role; however, studies regarding the opposite process, mesenchymal-epithelial transition, are scanty. We have previously shown that fibroblast growth factor-1 (FGF-1) inhibits several profibrogenic effects of TGF-beta 1. In this study, we examined the effects of FGF-1 on TGF-beta 1-induced EMT. A549 and RLE-6TN (human and rat) alveolar epithelial-like cell lines were stimulated with TGF-beta 1 for 72 h, and then, in the presence of TGF-beta 1, were cultured with FGF-1 plus heparin for an additional 48 h. After TGF-beta 1 treatment, epithelial cells acquired a spindle-like mesenchymal phenotype with a substantial reduction of E-cadherin and cytokeratins and concurrent induction of alpha-smooth muscle actin measured by real-time PCR, Western blotting, and immunocytochemistry. FGF-1 plus heparin reversed these morphological changes and returned the epithelial and mesenchymal markers to control levels. Signaling pathways analyzed by selective pharmacological inhibitors showed that TGF-beta 1 induces EMT through Smad pathway, while reversion by FGF-1 occurs through MAPK/ERK kinase pathway, resulting in ERK-1 phosphorylation and Smad2 dephosphorylation. These findings indicate that TGF-beta 1-induced EMT is reversed by FGF-1 and suggest therapeutic approaches to target this process in IPF.