Journal article

Expression and Activity of Phosphodiesterase Isoforms during Epithelial Mesenchymal Transition: The Role of Phosphodiesterase 4


Authors listKolosionek, Ewa; Savai, Rajkumar; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Guenther, Andreas; Grimminger, Friedrich; Seeger, Werner; Banat, Gamal Andre; Schermuly, Ralph Theo; Pullamsetti, Soni Savai

Publication year2009

Pages4751-4765

JournalMolecular Biology of the Cell

Volume number20

Issue number22

ISSN1059-1524

eISSN1939-4586

Open access statusGreen

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

PublisherAmerican 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.



Citation Styles

Harvard Citation styleKolosionek, 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 Citation styleKolosionek, 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



Keywords


CAMP-PHOSPHODIESTERASEFIBROSISINVOLVEMENTMESANGIAL CELLSPULMONARY-HYPERTENSIONSMOOTH-MUSCLE-CELLSTGF-BETA SIGNALSTUMOR-GROWTH

Last updated on 2025-10-06 at 09:52