Peroxisome proliferator-activated receptor γ promotes lymphocyte survival through its actions on cellular metabolic activities

Peroxisome proliferator-activated receptor gamma (PPART) is a metabolic regulator that plays an important role in sensitizing tissues to the action of insulin and in normalizing serum glucose and free fatty acids in type 2 diabetic patients. The receptor has also been implicated in the modulation of inflammatory responses, and ligands of PPAR gamma have been found to induce apoptosis in lymphocytes. However, apoptosis induction may not depend on the receptor, because high doses of PPAR gamma agonists are required for this process. Using cells containing or lacking PPAR gamma, we reported previously that PPAR gamma attenuates apoptosis induced by cytokline withdrawal in a murine lymphocytic cell line via a receptor-dependent mechanism. PPAR gamma exerts this effect by,enhancing the ability of cells to maintain their mitochondrial membrane potential during cytokine deprivation. In this report, we demonstrate that activation of PPAR gamma also protects cells from serum starvation-induced apoptosis in human T lymphoma cell lines. Furthermore, we show that the survival effect of PPAR gamma is mediated through its actions on cellular metabolic activities. In cytokine-deprived cells, PPAR gamma attenuates the decline in ATP level and. suppresses accumulation of reactive oxygen species (ROS). Moreover, PPAR gamma regulates ROS through its coordinated transcriptional control of proteins and enzymes involved in ROS scavenging, including uncoupling protein 2, catalase, and copper zinc superoxide dismutase. Our studies identify cell survival promotion as a novel activity of PPAR gamma and suggest that PPAR gamma may modulate cytokine withdrawal-induced activated T cell death.