Thiazolidinediones (TZDs) are insulin-sensitising drugs that are ligands for the nuclear receptor PPARgamma. 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 PPARgamma activation. Here we show that insulin-sensitising concentrations of the TZD rosiglitazone partially inhibit serum- or LPS- (but not PMA-) stimulated TNFalpha secretion from primary human monocytes, with an IC50 of around 50 nM. We also show that the observed effects are independent of PPARgamma-mediated regulation of the lipid phosphatase PTEN. Reversed stimulus specificity, IC50 in the insulin-sensitising range, and the fact that partial inhibition of TNFalpha secretion is also observed with a structurally unrelated PPARgamma agonist, GW7845, demonstrate a mechanism of action distinct from that observed with higher TZD concentrations. These findings thus represent the first report of a PPARgamma-dependent and therapeutically relevant anti-inflammatory action of TZDs in isolated human monocytes. (C) 2003 Elsevier Science (USA). All rights reserved.