PPAR Gamma agonists regulate tobacco smoke-induced toll like receptor 4 expression in alveolar macrophages

Background: Peroxisome proliferator-activated receptor-gamma (PPAR.) is a ligand-activated transcription factor that exerts multiple biological effects. Growing evidence suggests that PPAR. plays an important role in inflammation; however, the effects of this transcription factor on the inflammation caused by smoking are unclear. Methods: We measured the expression of inflammatory cytokines (leukotriene B4, LTB4 and interleukin 8, IL-8), PPAR. and toll-like receptors (TLR2 and TLR4) in alveolar macrophages (AMs) harvested from rats exposed to cigarette smoke (CS) for 3 months in vivo. Some of the rats were pre-treated with rosiglitazone (PPAR. agonist, 3 mg/kg/day, ip), rosiglitazone (3 mg/kg/day, ip) + BADGE (bisphenol A diglycidyl ether, a PPAR. antagonist, 30 mg/kg/day, ig), or BADGE alone (30 mg/kg/day, ig). We also measured the expression of PPAR., TLR2, TLR4 and nuclear factor-kappaB (NF-kappa B) in AMs gained from normal rats, which exposed to 5% CSE (cigarette smoke extract) for 12hrs, respectively pretreated with PBS, rosiglitazone (30 uM), rosiglitazone (30 uM) + BADGE (100 uM), 15d-PGJ2 (PPAR. agonist, 5 uM), 15d-PGJ2 (5 uM) + BADGE (100 uM), or BADGE (100 uM) alone for 30 min in vitro. Results: In vivo, rosiglitazone counteracted CS-induced LTB4 and IL-8 release and PPAR. downregulation, markedly lowering the expression of TLR4 and TLR2. In vitro, both rosiglitazone and 15d-PGJ2 inhibited CS-induced inflammation through the TLR4 signaling pathway. Conclusions: These results suggest that PPAR. agonists regulate inflammation in alveolar macrophages and may play a role in inflammatory diseases such as COPD.