Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma 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 (PPAR gamma) 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 PPAR gamma and TZDs in lymphocyte survival. PPAR gamma was up-regulated upon T cell activation. As previously reported, PPAR gamma 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 PPAR gamma-dependent transcription. Surprisingly, at concentrations that induce optimal transcriptional activation, TZD activation of PPAR gamma protected cells from apoptosis following growth factor withdrawal. The survival-enhancing effects depended on both the presence and activation of PPAR gamma. Measurements of mitochondrial potential revealed that PPAR gamma activation enhanced the ability of cells to maintain their mitochondrial potential. These data indicate that activation of PPAR gamma with TZDs can promote cell survival and suggest that PPAR gamma activation may potentially augment the immune responses of diabetic patients.