Blockade of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Exacerbates Type 1 Diabetes in NOD Mice
- Qing-Sheng Mi1,
- Dalam Ly1,
- S.-E. Lamhamedi-Cherradi2,
- Konstantin V. Salojin1,
- Li Zhou3,
- Marsha Grattan1,
- Craig Meagher1,
- Peter Zucker1,
- Youhai H. Chen2,
- James Nagle4,
- Dennis Taub4 and
- Terry L. Delovitch15
- 1Autoimmunity/Diabetes Group, the John P. Robarts Research Institute, London, Ontario, Canada
- 2Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- 3Neurosignaling Group, the John P. Robarts Research Institute, London, Ontario, Canada
- 4Lab of Immunology, National Institute on Aging/National Institutes of Health, Baltimore, Maryland
- 5Department 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 p27kip1. 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
- HSA, human serum albumin
- IFN, interferon
- IL, interleukin
- LPS, lipopolysaccharide
- NK, natural killer
- NIA, National Institute on Aging
- STZ, streptozotocin
- TCR, T-cell receptor
- TNF, tumor necrosis factor
- TRAIL, TNF-related apoptosis-inducing ligand
- TUNEL, transferase-mediated dUTP nick-end labeling
Footnotes
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- Accepted April 21, 2003.
- Received January 3, 2003.
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