Critical roles of tumor necrosis factor-related apoptosis-inducing ligand in type 1 diabetes.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of tumor cells but not most normal cells. Its roles in normal nontransformed tissues are not clear. To explore the potential roles of TRAIL in type 1 diabetes, we examined the consequences of TRAIL blockade or TRAIL deficiency in two animal models of autoimmune diabetes. In the first model, NOD mice received an injection of a soluble TRAIL receptor to block TRAIL function. This significantly accelerated the diabetes and increased the degree of autoimmune inflammation in both pancreatic islets and salivary glands. The GAD65-specific immune responses were also significantly enhanced in animals that received the soluble TRAIL receptor. In the second model, we treated normal and TRAIL-deficient C57BL/6 mice with multiple low-dose streptozotocin to induce diabetes. We found that both the incidence and the degree of islet inflammation were significantly enhanced in TRAIL-deficient animals. On the basis of these observations, we conclude that TRAIL deficiency accelerates autoimmune diabetes and enhances autoimmune responses.
Lamhamedi-Cherradi
Salah-Eddine
SE
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Zheng
Shijun
S
Tisch
Roland M
RM
Chen
Youhai H
YH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D003520:Cyclophosphamide; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007166:Immunosuppressive Agents; D007515:Islets of Langerhans / Q000276:immunology; D007527:Isoenzymes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2