Thiazolidinedione activation of peroxisome proliferator-activated receptor γ can enhance mitochondrial potential and promote cell survival

Thiazolidinediones (TZDs) are widely used for treatment of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPARgamma) is the molecular target of TZDs and is believed to mediate the apoptotic effects of this class of drugs in a variety of cell types, including B and T lymphocytes. The finding that TZDs induce lymphocyte death has raised concerns regarding whether TZDs might further impair immune functions in diabetics. To address this issue, we investigated the roles of PPARgamma and TZDs in lymphocyte survival. PPARgamma was up-regulated upon T cell activation. As previously reported, PPARgamma agonists induced T cell death in a dose-dependent manner. However, the concentrations of TZD needed to cause T cell death were above those needed to induce PPARgamma-dependent transcription. Surprisingly, at concentrations that induce optimal transcriptional activation, TZD activation of PPARgamma protected cells from apoptosis following growth factor withdrawal. The survival-enhancing effects depended on both the presence and activation of PPARgamma. Measurements of mitochondrial potential revealed that PPARgamma activation enhanced the ability of cells to maintain their mitochondrial potential. These data indicate that activation of PPARgamma with TZDs can promote cell survival and suggest that PPARgamma activation may potentially augment the immune responses of diabetic patients.