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Thiazolidinediones Are Partial Agonists for the Glucocorticoid Receptor

Endocrine Sciences Research Group (L.M., A.B., D.R.), Division of Cardiovascular and Endocrine Science, University of Manchester, Manchester M13 9PT, United Kingdom; Department of Experimental Pharmacology (M.T., A.I.), University of Naples Federico II, 80131 Naples, Italy; and Research Centre in Biochemical Pharmacology (F.D.), William Harvey Research Institute, John Vane Science Centre, London EC1M 6BQ, United Kingdom

Address all correspondence and requests for reprints to: David Ray, Endocrine Sciences Research Group, AV Hill Building, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. E-mail: david.w.ray{at}manchester.ac.uk; or Angela Ianaro, Department of Experimental Pharmacology, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy. E-mail: ianaro{at}unina.it.

Although thiazolidinediones were designed as specific peroxisome proliferator-activated receptor (PPAR)--ligands, there is evidence for some off-target effects mediated by a non-PPAR mechanism. Previously we have shown that rosiglitazone has antiinflammatory actions not explicable by activation of PPAR,but possibly by the glucocorticoid receptor (GR). Rosiglitazone induces nuclear translocation both of GR-green fluorescent protein, and endogenous GR in HeLa and U20S cells but with slower kinetics than dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser²¹¹), a GR ligand-binding-specific effect. Rosiglitazone drives luciferase expression from a simple glucocorticoid-response element containing reporter gene in a GR-dependent manner (EC₅₀ 4 µM), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits dexamethasone-driven reporter gene activity (IC₅₀ 2.9 µM) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPAR-null cells, suggesting both GR dependence and PPAR independence. Rosiglitazone also activates a GAL4-GR chimera, driving a upstream activating sequence promoter, demonstrating DNA template sequence independence and furthermore enhanced steroid receptor coactivator-1-GR interaction, measured by a mammalian two-hybrid assay. Both ciglitazone and pioglitazone, structurally related to rosiglitazone, show similar effects on the GR. The antiproliferative effect of rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of rosiglitazone action. Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the antidiabetic actions of rosiglitazone.