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The molecular mechanisms underlying the proinflammatory actions of thiazolidinediones in human macrophages.

Publication ,  Journal Article
Hall, JM; McDonnell, DP
Published in: Mol Endocrinol
August 2007

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

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Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

August 2007

Volume

21

Issue

8

Start / End Page

1756 / 1768

Location

United States

Related Subject Headings

  • Thiazolidinediones
  • Peroxisome Proliferator-Activated Receptors
  • Mice
  • Macrophages
  • Inflammation Mediators
  • Humans
  • Hela Cells
  • HeLa Cells
  • Endocrinology & Metabolism
  • Cell Line
 

Citation

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Hall, J. M., & McDonnell, D. P. (2007). The molecular mechanisms underlying the proinflammatory actions of thiazolidinediones in human macrophages. Mol Endocrinol, 21(8), 1756–1768. https://doi.org/10.1210/me.2007-0060
Hall, Julie M., and Donald P. McDonnell. “The molecular mechanisms underlying the proinflammatory actions of thiazolidinediones in human macrophages.Mol Endocrinol 21, no. 8 (August 2007): 1756–68. https://doi.org/10.1210/me.2007-0060.
Hall, Julie M., and Donald P. McDonnell. “The molecular mechanisms underlying the proinflammatory actions of thiazolidinediones in human macrophages.Mol Endocrinol, vol. 21, no. 8, Aug. 2007, pp. 1756–68. Pubmed, doi:10.1210/me.2007-0060.

Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

August 2007

Volume

21

Issue

8

Start / End Page

1756 / 1768

Location

United States

Related Subject Headings

  • Thiazolidinediones
  • Peroxisome Proliferator-Activated Receptors
  • Mice
  • Macrophages
  • Inflammation Mediators
  • Humans
  • Hela Cells
  • HeLa Cells
  • Endocrinology & Metabolism
  • Cell Line