Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
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.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type 2 membrane protein of the TNF superfamily. It preferentially induces apoptosis of tumor cells but not most normal cells, with the exception of hepatocytes, neural cells, and thymocytes, which are sensitive to TRAIL-induced apoptosis. In humans, TRAIL interacts with at least four membrane receptors that all belong to the TNF receptor superfamily. TRAIL receptor 1 (TRAIL-R1 or death receptor 4) and TRAIL receptor 2 (TRAIL-R2, death receptor 5, TRICK2, or KILLER) have cytoplasmic death domains, and can activate both caspases and nuclear factor (NF)-
B pathways. The other two receptors, TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2), have truncated death domains. They are not capable of activating caspase cascade but may activate NF-
B and block apoptosis. In addition, osteoprotegerin may be a soluble receptor for TRAIL, which can inhibit osteoclastogenesis and increase bone density. In contrast to these receptors in humans, only one membrane TRAIL receptor has been identified in mice, which shares the highest homology with human death receptor (DR) 5. The mouse decoy receptors share low homology with those of humans and do not have intracellular domains. Although TRAIL and its receptors are expressed in a variety of mouse and human tissues, their roles in health and diseases are not clear.
Type 1 diabetes is an autoimmune inflammatory disease of the pancreatic islets. In both human type 1 diabetes and its rodent models, pancreatic
-cells that produce insulin are selectively destroyed by infiltrating inflammatory cells. The cyclophosphamide (CY)-accelerated diabetes and the low-dose streptozotocin (STZ)-induced diabetes are putative mouse models of human type 1 diabetes. The disease can be induced by a single injection of CY in NOD mice or by multiple injections of low-dose STZ in susceptible strains of animals. Both models share many clinical and histologic features with human type 1 diabetes and require the participation of T-cells and macrophages. To explore the roles of TRAIL in diabetes, we studied these two disease models in animals that were either deficient in TRAIL or treated with a blocking TRAIL receptor. We found that TRAIL played a critical role in the pathogenesis of 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.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type 2 membrane protein of the TNF superfamily. It preferentially induces apoptosis of tumor cells but not most normal cells, with the exception of hepatocytes, neural cells, and thymocytes, which are sensitive to TRAIL-induced apoptosis. In humans, TRAIL interacts with at least four membrane receptors that all belong to the TNF receptor superfamily. TRAIL receptor 1 (TRAIL-R1 or death receptor 4) and TRAIL receptor 2 (TRAIL-R2, death receptor 5, TRICK2, or KILLER) have cytoplasmic death domains, and can activate both caspases and nuclear factor (NF)-
B pathways. The other two receptors, TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2), have truncated death domains. They are not capable of activating caspase cascade but may activate NF-
B and block apoptosis. In addition, osteoprotegerin may be a soluble receptor for TRAIL, which can inhibit osteoclastogenesis and increase bone density. In contrast to these receptors in humans, only one membrane TRAIL receptor has been identified in mice, which shares the highest homology with human death receptor (DR) 5. The mouse decoy receptors share low homology with those of humans and do not have intracellular domains. Although TRAIL and its receptors are expressed in a variety of mouse and human tissues, their roles in health and diseases are not clear.
Type 1 diabetes is an autoimmune inflammatory disease of the pancreatic islets. In both human type 1 diabetes and its rodent models, pancreatic
-cells that produce insulin are selectively destroyed by infiltrating inflammatory cells. The cyclophosphamide (CY)-accelerated diabetes and the low-dose streptozotocin (STZ)-induced diabetes are putative mouse models of human type 1 diabetes. The disease can be induced by a single injection of CY in NOD mice or by multiple injections of low-dose STZ in susceptible strains of animals. Both models share many clinical and histologic features with human type 1 diabetes and require the participation of T-cells and macrophages. To explore the roles of TRAIL in diabetes, we studied these two disease models in animals that were either deficient in TRAIL or treated with a blocking TRAIL receptor. We found that TRAIL played a critical role in the pathogenesis of diabetes.