PPAR gamma-dependent anti-inflammatory action of rosiglitazone in human monocytes: suppression of TNF alpha secretion is not mediated by PTEN regulation

• Published in: Biochemical and biophysical research communications Vol. 303; no. 3; pp. 782 - 787
• Main Authors: Hong, Guizhu, Davis, Bill, Khatoon, Nachima, Baker, Sharon F, Brown, John
• Format: Journal Article
• Language: English
• Published: United States 11.04.2003
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Chromones - pharmacology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Humans; In Vitro Techniques; Monocytes - drug effects; Monocytes - physiology; Morpholines - pharmacology; Oxazoles - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rosiglitazone; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - agonists; Transcription Factors - metabolism; Tumor Necrosis Factor-alpha - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tyrosine - analogs & derivatives; Tyrosine - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(03)00418-2

Thiazolidinediones (TZDs) are insulin-sensitising drugs that are ligands for the nuclear receptor PPAR gamma. They have been shown to inhibit PMA-stimulated secretion of TNFalpha from human monocytes, although only at concentrations well in excess of circulating levels observed during TZD therapy, suggesting a mechanism of action independent of PPAR gamma activation. Here we show that insulin-sensitising concentrations of the TZD rosiglitazone partially inhibit serum- or LPS- (but not PMA-) stimulated TNF alpha secretion from primary human monocytes, with an IC(50) of around 50nM. We also show that the observed effects are independent of PPAR gamma-mediated regulation of the lipid phosphatase PTEN. Reversed stimulus specificity, IC(50) in the insulin-sensitising range, and the fact that partial inhibition of TNF alpha secretion is also observed with a structurally unrelated PPAR gamma agonist, GW7845, demonstrate a mechanism of action distinct from that observed with higher TZD concentrations. These findings thus represent the first report of a PPAR gamma-dependent and therapeutically relevant anti-inflammatory action of TZDs in isolated human monocytes.