title: Differential ability of a thiazolidinedione PPARgamma agonist to attenuate cytokine secretion in primary microglia and macrophage-like cells.
abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are known to inhibit select pro-inflammatory changes in models of CNS and systemic inflammation. Recent reports suggest that these anti-inflammatory effects are due to mechanisms other than canonical nuclear receptor-mediated transcriptional alteration. Using primary microglia and the monocytic cell line, THP-1, we demonstrate that rosiglitazone, a PPARgamma-activating thiazolidinedione, decreases pro-inflammatory cytokine secretion as measured by ELISA. Cells were pre-treated with various thiazolidinediones, including rosiglitazone, prior to stimulation with lipopolysaccharide or phorbol 12-myristate 13-acetate (PMA) to stimulate cytokine production. Tumor necrosis factor alpha (TNFalpha) secretion was significantly inhibited in both primary microglia and THP-1 cells differentiated for 72 h in the presence of PMA to induce a macrophage-like phenotype. No reduction in TNFalpha secretion was observed in undifferentiated THP-1 cells with rosiglitazone pre-treatment. Electrophoretic mobility shift assay revealed no significant difference in PPARgamma activation between PMA-differentiated and undifferentiated THP-1 cells. When PMA-differentiated and undifferentiated THP-1 cells were treated with the irreversible PPARgamma antagonist, GW 9662, a significant, dose-dependent decrease in TNFalpha secretion was observed. These results suggest that the anti-inflammatory benefit of PPARgamma ligands occur independently of classical PPARgamma activation.
authors.affiliation: Department of Pharmacology, Physiology & Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Woster
authors.forename: Colin K
authors.initials: CK
authors.lastname: Combs
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077154:Rosiglitazone; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D008024:Ligands; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000072000:NF-KappaB Inhibitor alpha; D013755:Tetradecanoylphorbol Acetate