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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents



ID: 474508.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition: the role of phosphodiesterase 4
Authors:Kolosionek, E.; Savai, R.; Ghofrani, H. A.; Weissmann, N.; Guenther, A.; Grimminger, F.; Seeger, W.; Banat, G. A.; Schermuly, R. T.; Pullamsetti, S. S.
Date of Publication (YYYY-MM-DD):2009
Title of Journal:Mol Biol Cell
Volume:20
Issue / Number:22
Start Page:4751
End Page:65
Audience:Not Specified
Abstract / Description: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)-beta1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-beta1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-beta1 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-beta1 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-beta1-stimulated cells. Most importantly, treatment of TGF-beta1 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-beta1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-beta1 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.
Free Keywords:Animals; Biological Markers/metabolism; Cell Line; Cyclic Nucleotide Phosphodiesterases, Type 4/antagonists &; inhibitors/genetics/*metabolism; Epithelial Cells/cytology/physiology; Epithelium/*physiology; Gene Knockdown Techniques; Humans; Isoenzymes/genetics/*metabolism; Mesoderm/*physiology; Molecular Sequence Data; Phosphodiesterase Inhibitors/metabolism; Pulmonary Alveoli/cytology/physiology; RNA Interference; Reactive Oxygen Species/metabolism; Rolipram/metabolism; Signal Transduction/physiology; Smad Proteins/metabolism; Transforming Growth Factor beta1/metabolism; rho-Associated Kinases/antagonists & inhibitors/genetics/metabolism; rhoA GTP-Binding Protein/genetics/metabolism
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:University of Giessen Lung Centre, Giessen, Germany.
Identifiers:ISSN:1939-4586 (Electronic) 1059-1524 (Linking)
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=..
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