PPARγ-dependent anti-inflammatory action of rosiglitazone in human monocytes: suppression of TNFα secretion is not mediated by PTEN regulation

Thiazolidinediones (TZDs) are insulin-sensitising drugs that are ligands for the nuclear receptor PPARγ. They have been shown to inhibit PMA-stimulated secretion of TNFα from human monocytes, although only at concentrations well in excess of circulating levels observed during TZD therapy, suggesting a mechanism of action independent of PPARγ activation. Here we show that insulin-sensitising concentrations of the TZD rosiglitazone partially inhibit serum- or LPS- (but not PMA-) stimulated TNFα secretion from primary human monocytes, with an IC50 of around 50nM. We also show that the observed effects are independent of PPARγ-mediated regulation of the lipid phosphatase PTEN. Reversed stimulus specificity, IC50 in the insulin-sensitising range, and the fact that partial inhibition of TNFα secretion is also observed with a structurally unrelated PPARγ agonist, GW7845, demonstrate a mechanism of action distinct from that observed with higher TZD concentrations. These findings thus represent the first report of a PPARγ-dependent and therapeutically relevant anti-inflammatory action of TZDs in isolated human monocytes.