期刊
MOLECULAR BIOLOGY OF THE CELL
卷 20, 期 22, 页码 4751-4765出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E09-01-0019
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- Nycomed (Konstanz, Germany)
- Deutsche Forschungsgemeinschaft [KFO 118]
- European Commission [LSHM-CT-2005-018725]
- Justus-Liebig University (Giessen, Germany)
Epithelial-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-beta 1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-beta 1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-beta 1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and alpha-smooth muscle actin. Interestingly, TGF-beta 1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-beta 1-stimulated cells. Most importantly, treatment of TGF-beta 1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-beta 1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-beta 1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.
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