PPARγ agonists regulate tobacco smoke-induced Toll like receptor 4 expression in alveolar macrophages

Respir Res. 2014 Mar 11;15(1):28. doi: 10.1186/1465-9921-15-28.

Abstract

Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor that exerts multiple biological effects. Growing evidence suggests that PPARγ 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), PPARγ 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 (PPARγ agonist, 3 mg/kg/day, ip), rosiglitazone (3 mg/kg/day, ip) + BADGE (bisphenol A diglycidyl ether, a PPARγ antagonist, 30 mg/kg/day, ig), or BADGE alone (30 mg/kg/day, ig). We also measured the expression of PPARγ, TLR2, TLR4 and nuclear factor-kappaB (NF-κB) in AMs gained from normal rats, which exposed to 5% CSE (cigarette smoke extract) for 12 hrs, respectively pretreated with PBS, rosiglitazone (30 uM), rosiglitazone (30 uM) + BADGE (100 uM), 15 d-PGJ2 (PPARγ agonist, 5 uM), 15 d-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 PPARγ downregulation, markedly lowering the expression of TLR4 and TLR2. In vitro, both rosiglitazone and 15 d-PGJ2 inhibited CS-induced inflammation through the TLR4 signaling pathway.

Conclusions: These results suggest that PPARγ agonists regulate inflammation in alveolar macrophages and may play a role in inflammatory diseases such as COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Down-Regulation / genetics
  • Inhalation Exposure / adverse effects*
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / pathology
  • Male
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism*
  • Phagocytosis / drug effects
  • Phagocytosis / physiology
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Rosiglitazone
  • Smoking / adverse effects
  • Smoking / metabolism*
  • Smoking / pathology
  • Thiazolidinediones / pharmacology
  • Toll-Like Receptor 4 / biosynthesis
  • Toll-Like Receptor 4 / genetics*

Substances

  • PPAR gamma
  • Thiazolidinediones
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Rosiglitazone