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Peroxisome Proliferator-Activated Receptor Promotes Lymphocyte Survival through Its Actions on Cellular Metabolic Activities¹

Seung-Hee Jo^*, Chunyan Yang^*, Qi Miao^*, Michal Marzec, Mariusz A. Wasik, Pin Lu and Y. Lynn Wang^2,*

^* Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Immunoregulation Laboratory, Hospital of Special Surgery, New York, NY 10021

Peroxisome proliferator-activated receptor (PPAR) 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 have been found to induce apoptosis in lymphocytes. However, apoptosis induction may not depend on the receptor, because high doses of PPAR agonists are required for this process. Using cells containing or lacking PPAR, we reported previously that PPAR attenuates apoptosis induced by cytokine withdrawal in a murine lymphocytic cell line via a receptor-dependent mechanism. PPAR 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 also protects cells from serum starvation-induced apoptosis in human T lymphoma cell lines. Furthermore, we show that the survival effect of PPAR is mediated through its actions on cellular metabolic activities. In cytokine-deprived cells, PPAR attenuates the decline in ATP level and suppresses accumulation of reactive oxygen species (ROS). Moreover, PPAR 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 and suggest that PPAR may modulate cytokine withdrawal-induced activated T cell death.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a National Heart, Lung, and Blood Institute Career Award K08-HL068850 (to Y.L.W.).

² Address correspondence and reprint requests to Dr. Y. Lynn Wang, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 525 East 68th Street, Box 69, New York, NY 10021. E-mail address: lyw2001{at}med.cornell.edu

³ Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor; Ct, threshold cycle; 2DOG, 2-deoxyglucose; 15d-PGJ₂, 15-deoxy-^12,14-PGJ₂; CuZnSOD, copper-zinc-dependent superoxide dismutase; siRNA, small interfering RNA; DCF, 5-(and 6-)carboxy-2',7'-dichlorodihydrofluorescein diacetate; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; IAA, iodoacetic acid; PPRE, PPAR response element; ROS, reactive oxygen species; TZD, thiazolidinedione; UCP, uncoupling protein.

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