Biochemical Society Transactions vol:36 pages:328-333
the Biochemical Society Focused Meeting on Pancreatic beta-cell: birth, life and death location:, King's College London School of Medicine, London, UK date:3 - 4 December 2007
IFN gamma (interferon gamma), a cytokine typically secreted by infiltrating immune cells in insulitis in Type 1 diabetes, is by itself not detrimental to beta-cells, but, together with other cytokines, such as IL-1 beta (interleukin 1 beta) and TNF alpha (tumour necrosis factor alpha), or dsRNA (double-stranded RNA), it induces beta-cell apoptosis. The complex gene and protein networks that are altered by the combination of cytokines clearly point towards synergisms between these agents. IFN gamma acts mostly via JAK (Janus kinase) activation, with the transcription factors STAT-1 (signal transducer and activator of transcription-1) and IRF-1 (IFN gamma regulatory factor-1) playing a central role in the downstream pathway. The study of mice with a disruption of these transcription factors has revealed a possible dual role for IFN gamma in beta-cell destruction by cytokines or dsRNA. We demonstrated that the absence of STAT-1 from beta-cells completely protects against IFN gamma + IL-1 beta-and IFN gamma + dsRNA-mediated beta-cell death in vitro, whereas absence of IRF-1 does not prevent cytokine-incluced beta-cell apoptosis. In vivo, a lack of the IRF-1 gene in pancreatic islets even promotes low-dose streptozotocin-incluced diabetes, whereas lack of STAT-1 confers resistance against beta-cell death following low-dose streptozotocin-incluced diabetes. Additionally, IRF-1(-/-) islets are more sensitive to PNF (primary islet non-function) after transplantation in spontaneously diabetic NOD (non-obese diabetic) mice, whereas STAT-1(-/-) islets are fully protected. Moreover, proteomic analysis of beta-cells exposed to IFN gamma of IFN gamma + IL-1 beta confirms that very different pathways are activated by IFNy alone compared with the combination. we conclude that IFN gamma may play a dual role in immune-induced beta-cell destruction. Transcription factors drive this dual role, with STAT-1 driving beta-cell destruction and IRF-1 possibly playing a role in up-regulation of protective pathways induced by IFN gamma.