Rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J 2, PPARγ agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages

Abstract

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) ligands have the potential for use as anti-inflammatory agents in chronic airway diseases. We hypothesized that cigarette smoke (CS)-mediated pro-inflammatory cytokine release would be downregulated in the monocyte-macrophage cell line (MonoMac6) by synthetic and natural PPARγ ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPARγ ligand 15-deoxy-Δ 12,14-prostaglandin J2 led to increased cytokine (IL-8) release in response to either TNF-α or CS extract (CSE). However, exposure to rosiglitazone, a synthetic agonist, led to decreased TNF-α, but not CSE, mediated cytokine release. Cytokine release correlated with nuclear PPARγ localization; CSE reduced the amount of activated PPARγ located in the nucleus and formed aldehyde adducts as PPARγ protein carbonyls. Furthermore, it was shown that PPARγ interacts with the RelA/p65 subunit of NF-κB under TNF-α exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPARγ. Thus, these new data show that activation of PPARγ with natural or synthetic ligands have differential inhibitory effects on CS-mediated pro-inflammatory mediator release. These data have implications in designing therapies for treatment of COPD and pulmonary fibrosis. © 2008 Mary Ann Liebert, Inc.