Blockade of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Exacerbates Type 1 Diabetes in NOD Mice

Blockade of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Exacerbates Type 1 Diabetes in NOD Mice Qing-Sheng Mi 1 , Dalam Ly 1 , S.-E. Lamhamedi-Cherradi 2 , Konstantin V. Salojin 1 , Li Zhou 3 , Marsha Grattan 1 , Craig Meagher 1 , Peter Zucker 1 , Youhai H. Chen 2 , James Nagle 4 , Dennis Taub 4 and Terry L. Delovitch 1 5 1 Autoimmunity/Diabetes Group, the John P. Robarts Research Institute, London, Ontario, Canada 2 Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 3 Neurosignaling Group, the John P. Robarts Research Institute, London, Ontario, Canada 4 Lab of Immunology, National Institute on Aging/National Institutes of Health, Baltimore, Maryland 5 Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada Address correspondence and reprint requests to Dr. Terry L. Delovitch, Autoimmunity/Diabetes Group, the John P. Robarts Research Institute, 1400 Western Rd., London, Ontario N6G 2V4, Canada. E-mail: del{at}robarts.ca Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including pancreas and lymphocytes, and can induce apoptosis in various tumor cells but not in most normal cells. The specific roles of TRAIL in health and disease remain unclear. Here we show by cDNA array analyses that TRAIL gene expression is upregulated in pancreatic islets during the development of autoimmune type 1 diabetes in nonobese diabetic (NOD) mice and in Min6 islet β-cells activated by TNF-α + interferon-γ. However, stimulation of freshly isolated pancreatic islets or Min6 cells with TRAIL did not induce their apoptosis. TRAIL blockade exacerbates the onset of type 1 diabetes in NOD. Scid recipients of transferred diabetogenic T-cells and in cyclophosphamide-treated NOD mice. TRAIL inhibits the proliferation of NOD diabetogenic T-cells by suppressing interleukin (IL)-2 production and cell cycle progression, and this inhibition can be rescued in the presence of exogenous IL-2. cDNA array and Western blot analyses indicate that TRAIL upregulates the expression of the cdk inhibitor p27 kip1 . Our data suggest that TRAIL is an important immune regulator of the development of type 1 diabetes. AICD, activation-induced cell death CFSE, 5- and 6-carboxy-florescein diacetate succinimidyl ester cdk, cyclin-dependent kinase CY, cyclophosphamide EAE, experimental autoimmune encephalomyelitis