IFNγ (interferon γ), a cytokine typically secreted by infiltrating immune cells in insulitis in Type 1 diabetes, is by itself not detrimental to β-cells, but, together with other cytokines, such as IL-1β (interleukin 1β) and TNFα (tumour necrosis factor α), or dsRNA (double-stranded RNA), it induces β-cell apoptosis. The complex gene and protein networks that are altered by the combination of cytokines clearly point towards synergisms between these agents. IFNγ acts mostly via JAK (Janus kinase) activation, with the transcription factors STAT-1 (signal transducer and activator of transcription-1) and IRF-1 (IFNγ 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 IFNγ in β-cell destruction by cytokines or dsRNA. We demonstrated that the absence of STAT-1 from β-cells completely protects against IFNγ+IL-1β- and IFNγ+dsRNA-mediated β-cell death in vitro, whereas absence of IRF-1 does not prevent cytokine-induced β-cell apoptosis. In vivo, a lack of the IRF-1 gene in pancreatic islets even promotes low-dose streptozotocin-induced diabetes, whereas lack of STAT-1 confers resistance against β-cell death following low-dose streptozotocin-induced 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 β-cells exposed to IFNγ or IFNγ+IL-1β confirms that very different pathways are activated by IFNγ alone compared with the combination. We conclude that IFNγ may play a dual role in immune-induced β-cell destruction. Transcription factors drive this dual role, with STAT-1 driving β-cell destruction and IRF-1 possibly playing a role in up-regulation of protective pathways induced by IFNγ.

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