Gras Delphine, Chanez Pascal, Urbach Valérie, Vachier Isabelle, Godard Philippe, Bonnans Caroline
Service des Maladies Respiratoires, Institut National de la Santé et de la Recherche Médicale Unité 454, Centre Hospitalier Universitaire-Montpellier, France.
Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L970-8. doi: 10.1152/ajplung.90219.2008. Epub 2009 Apr 3.
Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPARgamma ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPARgamma agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), inhibited cell growth. RGZ and TGZ (10 microM) induced a rapid and transient intracellular Ca(2+) mobilization from thapsigargin-sensitive intracellular stores, whereas 15d-PGJ(2) (5 microM) did not induce any Ca(2+) signal. The PPARgamma antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-PGJ(2) 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 Ca(2+) 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(2+) signaling pathway.
噻唑烷二酮类药物（TZDs）是合成的过氧化物酶体增殖物激活受体γ（PPARγ）配体，广泛用于II型糖尿病的治疗。除了能够改善葡萄糖稳态外，TZDs还具有抗炎特性，并能抑制许多细胞的生长，尤其是癌性气道上皮细胞。然而，PPARγ配体对非恶性人支气管上皮细胞的功能作用从未被研究过。在本研究中，我们质疑PPARγ配体是否可能调节人支气管上皮细胞的增殖，并研究了其潜在的分子机制。我们发现合成的PPARγ激动剂罗格列酮（RGZ）和曲格列酮（TGZ）可诱导人支气管上皮细胞增殖，而内源性PPARγ配体15-脱氧-Δ（12,14）-前列腺素J2（15d-PGJ2）则抑制细胞生长。RGZ和TGZ（10 microM）可诱导从毒胡萝卜素敏感的细胞内储存库快速且短暂的细胞内Ca2+动员，而15d-PGJ2（5 microM）则不诱导任何Ca2+信号。PPARγ拮抗剂GW-9662不抑制任何生物学反应，但它可逆转15d-PGJ2对细胞生长的作用。使用逆转录聚合酶链反应（RT-PCR），我们在人支气管上皮细胞中检测到GPR40受体的mRNA表达，GPR40受体是一种最近被鉴定为游离脂肪酸和TZDs受体的G蛋白偶联受体。小干扰RNA下调GPR40导致对TZDs诱导的Ca2+动员和增殖的显著抑制。本研究为抗糖尿病药物TZDs通过激活GPR40受体在非恶性人支气管上皮细胞中的增殖作用提供了证据，该作用涉及细胞内Ca2+信号通路。
