Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. PPARgamma forms a heterodimer with the retinoid X receptor and upon ligand-activation binds to the PPAR response element in the promoter of genes to allow transcription. The class of insulin-sensitizing drugs known as thiazolidinediones have been identified as specific PPARgamma agonists that have allowed the characterization of many genes regulated by PPARgamma. Thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone. In addition to these synthetic agonists, cyclopentenone prostaglandins of the J2 series have been identified as natural ligands for PPARgamma. Several in vitro and in vivo studies have demonstrated that pharmacological activation of PPARgamma by 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2) or thiazolidinediones has anti-inflammatory effects. This article provides an overview of the role of PPARgamma in regulating the inflammatory response and emphasizes the potential efficacy of PPARgamma ligands as novel therapeutic approaches beyond diabetes in sepsis, inflammation, and reperfusion injury.
Zingarelli
Basilia
B
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and the College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229, USA. basilia.zingarelli@cchmc.org
Cook
James A
JA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D049109:Cell Proliferation; D003517:Cyclopentanes / Q000737:chemistry; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015427:Reperfusion Injury; D047488:Retinoid X Receptors / Q000737:chemistry; D018805:Sepsis / Q000188:drug therapy*; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000378:metabolism; D014158:Transcription, Genetic
D000893:Anti-Inflammatory Agents; D003517:Cyclopentanes; D007328:Insulin; D008024:Ligands; D047495:PPAR gamma; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; C013905:cyclopentenone