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

Gras D, Chanez P, Urbach V, Vachier I, Godard P, Bonnans C. Thiazolidinediones induce proliferation of human bronchial epithelial cells through the GPR4O receptor. Am J Physiol Lung Cell Mol Physiol 296: L970-L978, 2009. First published April 3, 2009; doi: 10.1152/ajplung.90219.2008.-Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor-γ (PPARγ) ligands that are widely used in type 11 diabetes treatment. In addition to their ability to improve glucose homeostasis, TZDs possess antiinflammatory properties and inhibit growth of many cells, particularly cancerous airway epithelial cells. However, the functional effects of PPARγ ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPAR-γ ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPAR-γ agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPARγ ligand, 15deoxy-Δ[sup12.14]-prostaglandin J[sub2] (15d-PGJ[sub2]), inhibited cell growth. RGZ and TGZ (10 μM) induced a rapid and transient intracellular Ca[sup2+] mobilization from thapsigargin-sensitive intracellular stores, whereas lsd-PGJ[sub2] (5 μM) did not induce any Ca[sup2+] signal. The PPARγ antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-PGJ[sub2] on cell growth. Using RT-PCR, we detected mRNA expression of the GPR4O receptor, a G proteincoupled receptor recently identified as a receptor for free fatty acids and TZDs, in human bronchial epithelial cells. Downregulation of GPR4O by small-interfering RNA led to a significant inhibition of TZD-induced Ca[sup2+] 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 Ca[sup2+] signaling pathway. [ABSTRACT FROM AUTHOR]