Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages.
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.
Caito
Samuel
S
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York 14642. USA.
Yang
Se-Ran
SR
Kode
Aruna
A
Edirisinghe
Indika
I
Rajendrasozhan
Saravanan
S
Phipps
Richard P
RP
Rahman
Irfan
I
D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000077154:Rosiglitazone; D012906:Smoke; D012907:Smoking / Q000503:physiopathology*; D045162:Thiazolidinediones / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D016207:Cytokines; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; D016209:Interleukin-8; D047495:PPAR gamma; D012906:Smoke; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015230:Prostaglandin D2