The Molecular Mechanisms Underlying the Proinflammatory Actions of Thiazolidinediones in Human Macrophages
Abstract It is hypothesized that the antiinflammatory actions of peroxisome proliferator-activated receptors (PPARs) may explain the protective effect of these receptors in diabetes, atherosclerosis, cancer, and other inflammatory diseases. However, emerging evidence for proinflammatory activities of activated PPARs is concerning in light of new studies that associate PPAR modulators with an increased incidence of both cardiovascular events in humans and the sporadic formation of tumors in rodents. In an attempt to define the role of each PPAR subtype in inflammation, we made the unexpected observation that human PPARδ is a positive regulator of inflammatory responses in both monocytes and macrophages. Notably, TNFα-stimulated cells administered PPARδ agonists express and secrete elevated levels of inflammatory cytokines. Most surprising, however, was the finding that thiazolidinediones (TZDs) and other known PPARγ ligands display different degrees of proinflammatory activities in a PPARγ- and PPARα-independent manner via their ability to augment PPARδ signaling. A series of mechanistic studies revealed that TZDs, at clinically relevant concentrations, bind and activate the transcriptional activity of PPARδ. Collectively, these studies suggest that the observed proinflammatory and potentially deleterious effects of PPARγ ligands may be mediated through an off-target effect on PPARδ. These studies highlight the need for PPAR modulators with increased receptor subtype specificity. Furthermore, they suggest that differences in systemic exposure and consequently in the activation of PPARγ and PPARδ may explain why TZDs can exhibit both inflammatory and antiinflammatory activities in humans.