alexa Differential ability of a thiazolidinedione PPARgamma agonist to attenuate cytokine secretion in primary microglia and macrophage-like cells.


Journal of Clinical Toxicology

Author(s): Woster AP, Combs CK

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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. This article was published in J Neurochem and referenced in Journal of Clinical Toxicology

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