Critical Roles of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand in Type 1 Diabetes

Critical Roles of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand in Type 1 Diabetes Salah-Eddine Lamhamedi-Cherradi 1 , Shijun Zheng 1 , Roland M. Tisch 2 and Youhai H. Chen 1 1 Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 2 Department of Microbiology and Immunology, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina Address correspondence and reprint requests to Youhai H. Chen, 653 BRB-II/III, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: yhc{at}mail.med.upenn.edu Abstract 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. CY, cyclophosphamide DR, death receptor ELISA, enzyme-linked immunosorbent assay HAS, human serum albumin IFN-γ, γ-interferon IL, interleukin i.p., intraperitoneally LPS, lipopolysaccharide NF, nuclear factor sDR5, soluble DR5 STZ, streptozotocin TNF, tumor necrosis factor TRAIL, tumor necrosis factor–related apoptosis-inducing ligand Footnotes Accepted May 21, 2003. Received January 9, 2003. DIABETES