Regulation of cigarette smoke-induced toll-like receptor 4 expression by peroxisome proliferator-activated receptor-gamma agonists in bronchial epithelial cells.

BACKGROUND AND OBJECTIVE: This study was designed to determine the effects of peroxisome proliferator-activated receptor-gamma (PPARγ) on airway inflammatory response to cigarette smoke (CS) exposure.

METHODS: For the in vivo experiments, 50 male Wistar rats were randomly assigned to one of four groups and were exposed to CS and pretreatment with a PPARγ agonist, rosiglitazone or a vehicle (saline). PPARγ antagonist bisphenol A diglycidyl ether (BADGE) or saline was administered before rosiglitazone treatment. Leukotriene B4 (LTB4) and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay. PPARγ and toll-like receptor 4 (TLR4) expression levels were assessed by immunohistochemistry and real-time polymerase chain reaction. For the in vitro experiments, human bronchial epithelial cells were stimulated with CS or phosphate buffer saline, pretreated with PPARγ agonist rosiglitazone or 15-deoxy-(Δ12,14)-PG J2 before CS exposure. BADGE was administered prior to the agonist treatment. PPARγ, TLR4 and inhibitor of κB (IκBα) expression levels were assessed by Western bot.

RESULTS: CS exposure decreased PPARγ expression, as well as increased IL-8, LTB4 and TLR4 expression levels in bronchial epithelial cells in vivo and in vitro. Moreover, PPARγ ligands counteracted CS-induced airway inflammation by reducing IL-8 and LTB4 expression levels that are associated with TLR4 and nuclear factor-kappa B (NF-κB).

CONCLUSION: CS exposure increased the pro-inflammatory activity of bronchial epithelial cells by affecting PPARγ expression. Moreover, PPARγ may play a significant role as a modulator of the TLR4-dependent inflammatory pathway through NF-κB in bronchial epithelial cells.