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First published on January 31, 2005; DOI: 10.1124/mol.104.004895

0026-895X/05/6705-1620-1628$20.00
Mol Pharmacol 67:1620-1628, 2005

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ORIGINAL ARTICLE

Mechanism of the Anti-Inflammatory Effect of Thiazolidinediones: Relationship with the Glucocorticoid Pathway

Armando Ialenti, Gianluca Grassia, Paola Di Meglio, Pasquale Maffia, Massimo Di Rosa, and Angela Ianaro

Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy

Abstract

The glucocorticoid receptor (GR) and peroxisome proliferator-activated receptors (PPARs) play important roles in both physiological and pathological conditions such as cell differentiation, lipolysis, control of glucose metabolism, immunity, and inflammation. In fact, recent studies suggest that the thiazolidinedione (TZD) class of PPAR-{gamma} ligands, like glucocorticoids, may also be clinically beneficial in several inflammatory diseases, even if the molecular mechanisms responsible for these activities have not yet been clarified. In this study, by using a murine model of inflammation, the carrageenin-induced paw edema in mouse, we show that the anti-inflammatory activity exhibited by the PPAR-{gamma} agonists rosiglitazone and ciglitazone is reversed by the GR antagonist RU486 (17{beta}-hydroxy-11{beta}-[4-dimethylamino phenyl]-17{alpha}-[1-propynyl]estra-4,9-dien-3-one). Moreover, by using a conditional GR null cell line, we demonstrate, for the first time to our knowledge, that one of the possible mechanisms explaining the anti-inflammatory activity of TZDs is their ability to activate GR nuclear translocation. In addition, by using J774 cell line lacking PPAR-{gamma}, we demonstrate that PPAR-{gamma} expression could not be essential for TZD-mediated GR nuclear translocation, thus explaining, at least in part, the molecular mechanism underlying their anti-inflammatory activity.

Received July 12, 2004; accepted January 31, 2005

Address correspondence to: Dr. A. Ianaro, Department of Experimental Pharmacology, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy. E-mail: ianaro{at}unina.it




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