We have investigated the potential use of
peroxisome proliferator-activated receptor gamma (
PPARgamma) 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
PPARgamma agonists. Although 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) at micromolar concentrations significantly inhibited the production of
TNF-alpha and
IL-6, four other high affinity
PPARgamma 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
PPARgamma or when the murine macrophage cell line RAW 264.7 was used. Furthermore, saturating concentrations of a potent
PPARgamma ligand not only failed to block
cytokine production, but also were unable to block the inhibitory activity of
15d-PGJ2. Thus, activation of
PPARgamma does not appear to inhibit the production of
cytokines by either monocytes or macrophages, and the inhibitory effect observed with
15d-PGJ2 is most likely mediated by a
PPARgamma-independent mechanism. To examine the anti-inflammatory activity of
PPARgamma 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
PPARgamma in leukocytes will not be useful for the treatment of acute
inflammation.