title: Mechanism of the anti-inflammatory effect of thiazolidinediones: relationship with the glucocorticoid pathway.
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.
authors.affiliation: Department of Experimental Pharmacology, University of Naples Federico II, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Ialenti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Grassia
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.forename: Pasquale
authors.initials: P
authors.lastname: Maffia
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Rosa
authors.forename: Angela
authors.initials: A
authors.lastname: Ianaro
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004487:Edema / Q000188:drug therapy* / Q000378:metabolism; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D045162:Thiazolidinediones