Although thiazolidinediones were designed as specific PPAR-ligands there is evidence for some off-target effects mediated by a non-PPAR mechanism. Previously we have shown that Rosiglitazone has anti-inflammatory actions not explicable by activation of PPAR, but possibly by the glucocorticoid receptor (GR).

Rosiglitazone induces nuclear translocation both of GR-GFP, 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 GRE containing reporter gene in a GR-dependent manner (EC50 4µM), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits Dexamethasone driven reporter gene activity (IC50 2.9µM) 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 UAS promoter, demonstrating DNA template sequence independence, and furthermore enhanced SRC1-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 anti-diabetic actions of Rosiglitazone.