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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/6/L970    most recent 90219.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gras, D. Articles by Bonnans, C. PubMed PubMed Citation Articles by Gras, D. Articles by Bonnans, C.

Thiazolidinediones induce proliferation of human bronchial epithelial cells through the GPR40 receptor

Service des Maladies Respiratoires, Institut National de la Santé et de la Recherche Médicale Unité 454, Centre Hospitalier Universitaire-Montpellier, France

Submitted 5 March 2008 ; accepted in final form 1 April 2009

Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor- (PPAR) ligands that are widely used in type II diabetes treatment. In addition to their ability to improve glucose homeostasis, TZDs possess anti-inflammatory properties and inhibit growth of many cells, particularly cancerous airway epithelial cells. However, the functional effects of PPAR ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPAR ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPAR agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPAR ligand, 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂), inhibited cell growth. RGZ and TGZ (10 µM) induced a rapid and transient intracellular Ca²⁺ mobilization from thapsigargin-sensitive intracellular stores, whereas 15d-PGJ₂ (5 µM) did not induce any Ca²⁺ signal. The PPAR antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-PGJ₂ on cell growth. Using RT-PCR, we detected mRNA expression of the GPR40 receptor, a G protein-coupled receptor recently identified as a receptor for free fatty acids and TZDs, in human bronchial epithelial cells. Downregulation of GPR40 by small-interfering RNA led to a significant inhibition of TZD-induced Ca²⁺ mobilization and proliferation. This study provides evidence for the proliferative effect of anti-diabetic drug TZDs in nonmalignant human bronchial epithelial cells through GPR40 receptor activation, involving an intracellular Ca²⁺ signaling pathway.

airway epithelium; glitazone; calcium; peroxisome proliferator-activated receptor-; G protein receptor 40