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Troglitazone attenuates TGF-?1-induced EMT in alveolar epithelial cells via a PPAR?-independent mechanism.

ABSTRACT: 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)-?1-induced EMT in primary rat AEC and an alveolar epithelial type II (AT2) cell line (RLE-6TN). TGF-?1 (2.5 ng/mL) induced EMT in both cell types, as evidenced by acquisition of spindle-like morphology, increased expression of the mesenchymal marker ?-smooth muscle actin (?-SMA) and downregulation of the tight junctional protein zonula occludens-1 (ZO-1). Concurrent treatment with troglitazone (or rosiglitazone), ameliorated effects of TGF-?1. Furthermore, following stimulation with TGF-?1 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-?1-induced phosphorylation of Akt and glycogen synthase kinase (GSK)-3?, but also inhibited nuclear translocation of ?-catenin, phosphorylation of Smad2 and Smad3 and upregulation of the EMT-associated transcription factor SNAI1. These results demonstrate inhibitory actions of troglitazone on TGF-?1-induced EMT in AEC via a PPAR?-independent mechanism likely through inhibition of ?-catenin-dependent signaling downstream of TGF-?1, supporting a role for interactions between TGF-? and Wnt/?-catenin signaling pathways in EMT.

SUBMITTER: Zhou B

PROVIDER: S-EPMC3380041 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Troglitazone attenuates TGF-β1-induced EMT in alveolar epithelial cells via a PPARγ-independent mechanism.

Zhou Beiyun B Buckley Stephen T ST Patel Vipul V Liu Yixin Y Luo Jiao J Krishnaveni Manda Sai MS Ivan Mihaela M DeMaio Lucas L Kim Kwang-Jin KJ Ehrhardt Carsten C Crandall Edward D ED Borok Zea Z

PloS one 20120620 6

Peroxisome proliferator activated receptor γ (PPARγ) 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 PPARγ agonist, on transforming growth factor (TGF)-β1-induced EMT in primary rat AEC and an alveolar epithelial type II (AT2) cell line (RL ...[more]

PMID: 22745681

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Project description:Pulmonary fibrosis is a disease in which lung tissues become fibrous and thereby causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract, secreting inflammatory cytokines, which subsequently leads to the development of pulmonary fibrosis. Aesculetin, a major component of the sancho tree and chicory, is known to biologically have antioxidant and anti-inflammatory effects. Human alveolar epithelial A549 cells were cultured for 24 h in conditioned media of THP-1 monocyte-derived macrophages (mCM) with 1-20 ?M aesculetin. Micromolar aesculetin attenuated the cytotoxicity of mCM containing inflammatory tumor necrosis factor-? (TNF)-? and interleukin (IL)-8 as major cytokines. Aesculetin inhibited alveolar epithelial induction of the mesenchymal markers in mCM-exposed/IL-8-loaded A549 cells (?47-51% inhibition), while epithelial markers were induced in aesculetin-treated cells subject to mCM/IL-8 (?1.5-2.3-fold induction). Aesculetin added to mCM-stimulated A549 cells abrogated the collagen production and alveolar epithelial CXC-chemokine receptor 2 (CXCR2) induction. The production of matrix metalloproteinase (MMP) proteins in mCM-loaded A549 cells was reduced by aesculetin (?52% reduction), in parallel with its increase in tissue inhibitor of metalloproteinases (TIMP) proteins (?1.8-fold increase). In addition, aesculetin enhanced epithelial induction of tight junction proteins in mCM-/IL-8-exposed cells (?2.3-2.5-fold induction). The inhalation of polyhexamethylene guanidine (PHMG) in mice accompanied neutrophil predominance in bronchoalveolar lavage fluid (BALF) and macrophage infiltration in alveoli, which was inhibited by orally administrating aesculetin to mice. Treating aesculetin to mice alleviated PHMG-induced IL-8-mediated subepithelial fibrosis and airway barrier disruption. Taken together, aesculetin may antagonize pulmonary fibrosis and alveolar epithelial barrier disruption stimulated by the infiltration of monocyte-derived macrophages, which is typical of PHMG toxicity, involving interaction of IL-8 and CXCR2. Aesculetin maybe a promising agent counteracting macrophage-mediated inflammation-associated pulmonary disorders.

Dataset Information

Troglitazone attenuates TGF-?1-induced EMT in alveolar epithelial cells via a PPAR?-independent mechanism.

Publications

Troglitazone attenuates TGF-β1-induced EMT in alveolar epithelial cells via a PPARγ-independent mechanism.

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