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The Molecular Mechanisms Underlying the Proinflammatory Actions of Thiazolidinediones in Human Macrophages

Duke University Medical Center, Department of Pharmacology and Cancer Biology, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Donald P. McDonnell, Ph.D., Duke University Medical Center, Pharmacology and Cancer Biology, Box 3813, Durham, North Carolina 27710. E-mail: donald.mcdonnell{at}duke.edu.

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 PPAR is a positive regulator of inflammatory responses in both monocytes and macrophages. Notably, TNF-stimulated cells administered PPAR agonists express and secrete elevated levels of inflammatory cytokines. Most surprising, however, was the finding that thiazolidinediones (TZDs) and other known PPAR ligands display different degrees of proinflammatory activities in a PPAR- and PPAR-independent manner via their ability to augment PPAR signaling. A series of mechanistic studies revealed that TZDs, at clinically relevant concentrations, bind and activate the transcriptional activity of PPAR. Collectively, these studies suggest that the observed proinflammatory and potentially deleterious effects of PPAR ligands may be mediated through an off-target effect on PPAR. 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 PPAR and PPAR may explain why TZDs can exhibit both inflammatory and antiinflammatory activities in humans.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ

Ligands:   Rosiglitazone

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