Activation of peroxisome proliferator-activated receptor γ does not inhibit IL-6 or TNF-α responses of macrophages to lipopolysaccharide in vitro or in vivo

We have investigated the potential use of peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists as anti-inflammatory agents in cell-based assays and in a mouse model of endotoxemia, Human peripheral blood monocytes were treated with LPS or PMA and a variety of PPAR gamma agonists, Although 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) at micromolar concentrations significantly inhibited the production of TNF-alpha and IL-6, four other high affinity PPAR gamma ligands failed to affect cytokine production. Similar results were obtained when the monocytes were allowed to differentiate in culture into macrophages that expressed significantly higher levels of PPAR gamma or when the murine macrophage cell line RAW 264.7 was used. Furthermore, saturating concentrations of a potent PPAR gamma ligand not only failed to black cytokine production, but also were unable to block the inhibitory activity of 15d-PGJ(2), Thus, activation of PPAR gamma does not appear to inhibit the production of cytokines by either monocytes or macrophages, and the inhibitory effect observed with 15d-PGJ(2) is most likely mediated by a PPAR gamma-independent mechanism, To examine the anti-inflammatory activity of PPAR gamma agonists in vivo, db/db mice were treated with a potent thiazolidinedione that lowered their elevated blood glucose and triglyceride levels as expected. When thiazolidinedione-treated mice were challenged with LPS, they displayed no suppression of cytokine production. Rather, their blood levels of TNF-alpha and IL-6 were elevated beyond the levels observed in control db/db mice challenged with LPS. Comparable results were obtained with the corresponding lean mice. Our data suggest that compounds capable of activating PPAR gamma in leukocytes will not be useful for the treatment of acute inflammation.