Journalartikel

Jahr der Veröffentlichung: 2009

Seiten: 4751-4765

Zeitschrift: Molecular Biology of the Cell

Bandnummer: 20

Heftnummer: 22

ISSN: 1059-1524

eISSN: 1939-4586

Open Access Status: Green

DOI Link: https://doi.org/10.1091/mbc.E09-01-0019

Verlag: American Society for Cell Biology

Abstract: 
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.

Harvard-Zitierstil: Kolosionek, E., Savai, R., Ghofrani, H., Weissmann, N., Guenther, A., Grimminger, F., et al. (2009) Expression and Activity of Phosphodiesterase Isoforms during Epithelial Mesenchymal Transition: The Role of Phosphodiesterase 4, Molecular Biology of the Cell, 20(22), pp. 4751-4765. https://doi.org/10.1091/mbc.E09-01-0019

APA-Zitierstil: Kolosionek, E., Savai, R., Ghofrani, H., Weissmann, N., Guenther, A., Grimminger, F., Seeger, W., Banat, G., Schermuly, R., & Pullamsetti, S. (2009). Expression and Activity of Phosphodiesterase Isoforms during Epithelial Mesenchymal Transition: The Role of Phosphodiesterase 4. Molecular Biology of the Cell. 20(22), 4751-4765. https://doi.org/10.1091/mbc.E09-01-0019