Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice.
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 beta-cells activated by TNF-alpha + interferon-gamma. 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.
Mi
Qing-Sheng
QS
Autoimmunity/Diabetes Group, the John P. Robarts Research Institute, London, Ontario, Canada.
Ly
Dalam
D
Lamhamedi-Cherradi
S-E
SE
Salojin
Konstantin V
KV
Zhou
Li
L
Grattan
Marsha
M
Meagher
Craig
C
Zucker
Peter
P
Chen
Youhai H
YH
Nagle
James
J
Taub
Dennis
D
Delovitch
Terry L
TL
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007515:Islets of Langerhans / Q000473:pathology / Q000502:physiology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D013601:T-Lymphocytes / Q000166:cytology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27