Rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2, PPARγ agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages

Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) 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 PPAR gamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPAR gamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) led to increased cytokine (IL-8) release in response to either TNF-alpha or CS extract (CSE). However, exposure to rosiglitazone, a synthetic agonist, led to decreased TNF-alpha, but not CSE, mediated cytokine release. Cytokine release correlated with nuclear PPAR gamma localization; CSE reduced the amount of activated PPAR gamma located in the nucleus and formed aldehyde adducts as PPAR gamma protein carbonyls. Furthermore, it was shown that PPAR gamma interacts with the RelA/p65 subunit of NF-kB under TNF-alpha exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPAR gamma. Thus, these new data show that activation of PPAR gamma 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.