Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages

Antioxid Redox Signal. 2008 Feb;10(2):253-60. doi: 10.1089/ars.2007.1889.


Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) 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 PPARgamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2 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 PPARgamma localization; CSE reduced the amount of activated PPARgamma located in the nucleus and formed aldehyde adducts as PPARgamma protein carbonyls. Furthermore, it was shown that PPARgamma interacts with the RelA/p65 subunit of NF-kappaB under TNF-alpha exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPARgamma. Thus, these new data show that activation of PPARgamma 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Cytokines / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Immunologic Factors / pharmacology*
  • Interleukin-8 / metabolism
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Monocytes / drug effects
  • Monocytes / physiology*
  • PPAR gamma / agonists*
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology
  • Protein Processing, Post-Translational / drug effects
  • Rosiglitazone
  • Smoke*
  • Smoking / physiopathology*
  • Thiazolidinediones / pharmacology*


  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Cytokines
  • Hypoglycemic Agents
  • Immunologic Factors
  • Interleukin-8
  • PPAR gamma
  • Smoke
  • Thiazolidinediones
  • Rosiglitazone
  • Prostaglandin D2