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PLoS By Category | Recent
PLoS Articles
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Molecular Biology - Physiology - Respiratory Medicine
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Troglitazone Attenuates TGF-ß1-Induced EMT in Alveolar Epithelial Cells via a PPAR?-Independent Mechanism
Published:
Wednesday, June 20, 2012
Author:
Beiyun Zhou et al.
by Beiyun Zhou, Stephen T. Buckley, Vipul Patel, Yixin Liu, Jiao Luo, Manda Sai Krishnaveni, Mihaela Ivan, Lucas DeMaio, Kwang-Jin Kim, Carsten Ehrhardt, Edward D. Crandall, Zea Borok
Peroxisome proliferator activated receptor ? (PPAR?) agonists are effective antifibrotic agents in a number of tissues. Effects of these agents on epithelial-mesenchymal transition (EMT) of primary alveolar epithelial cells (AEC) and potential mechanisms underlying effects on EMT have not been well delineated. We examined effects of troglitazone, a synthetic PPAR? agonist, on transforming growth factor (TGF)-ß1-induced EMT in primary rat AEC and an alveolar epithelial type II (AT2) cell line (RLE-6TN). TGF-ß1 (2.5 ng/mL) induced EMT in both cell types, as evidenced by acquisition of spindle-like morphology, increased expression of the mesenchymal marker a-smooth muscle actin (a-SMA) and downregulation of the tight junctional protein zonula occludens-1 (ZO-1). Concurrent treatment with troglitazone (or rosiglitazone), ameliorated effects of TGF-ß1. Furthermore, following stimulation with TGF-ß1 for 6 days, troglitazone reversed EMT-related morphological changes and restored both epithelial and mesenchymal markers to control levels. Treatment with GW9662 (an irreversible PPAR? antagonist), or overexpression of a PPAR? dominant negative construct, failed to inhibit these effects of troglitazone in AEC. Troglitazone not only attenuated TGF-ß1-induced phosphorylation of Akt and glycogen synthase kinase (GSK)-3ß, but also inhibited nuclear translocation of ß-catenin, phosphorylation of Smad2 and Smad3 and upregulation of the EMT-associated transcription factor SNAI1. These results demonstrate inhibitory actions of troglitazone on TGF-ß1-induced EMT in AEC via a PPAR?-independent mechanism likely through inhibition of ß-catenin-dependent signaling downstream of TGF-ß1, supporting a role for interactions between TGF-ß and Wnt/ß-catenin signaling pathways in EMT.
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