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• W4313365525 abstract "Abstract Aims/hypothesis Type 1 diabetes is characterised by pancreatic islet inflammation and autoimmune-driven pancreatic beta cell destruction. Type I interferons, such as IFNα, are key players in early human type 1 diabetes pathogenesis, as the activation of the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway induces inflammation, a long-lasting MHC class I overexpression, endoplasmic reticulum (ER) stress, and beta cell apoptosis (in synergy with IL-1β). As TYK2 inhibition has been suggested as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect beta cells against the damaging effects of IFNα and other proinflammatory cytokines (i.e. IFNγ and IL-1β). Methods Inflammation, ER stress, and apoptosis were evaluated by real-time PCR, immunoblot, immunofluorescence, and nuclear dyes. The promoter activity was assessed by luciferase assay and insulin secretion and content by ELISA. All experiments were performed in the human EndoC- βH1 cell line. Results Pre-treatment with deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 phosphorylation and protein expression as well as MHC class I hyperexpression, in a dose-dependent manner without affecting beta cell survival and function. Comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signalling pathway. Pre-treatment with deucravacitinib protected beta cells from the pro-apoptotic and proinflammatory effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially revert apoptosis and inflammation in cells previously treated with IFNα + IL-1β or IFNγ + IL-1β. Conclusions/interpretation Our findings suggest that, by protecting beta cells against the deleterious effects of proinflammatory cytokines without affecting beta cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes. Research in context What is already known about this subject? In type 1 diabetes, pancreatic beta cells are killed by the immune system In early insulitis, type I interferons are crucial for the dialogue between the immune system and pancreatic beta cells Activation of the TYK2-STAT pathway by IFNα induces inflammation, HLA class I overexpression, ER stress, and beta cell apoptosis. What is the key question? Could the TYK2 inhibitor deucravacitinib prevent the deleterious effects of IFNα and other cytokines in beta cells? What are the new findings? Deucravacitinib prevented IFNα effects in a dose-dependent manner without affecting beta cell function and survival Pre-treatment with deucravacitinib protected beta cells against apoptosis and inflammation induced by two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β Addition of deucravacitinib to cells pre-treated with IFNα + IL-1β or IFNγ + IL-1β partially reverted apoptosis and inflammation induced by these cytokines How might this impact on clinical practice in the foreseeable future? Due to its protective effect against proinflammatory cytokines in beta cells, our findings suggest that deucravacitinib could be repurposed for the prevention or treatment of type 1 diabetes." @default.
• W4313365525 created "2023-01-06" @default.
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• W4313365525 date "2022-12-29" @default.
• W4313365525 modified "2023-09-30" @default.
• W4313365525 title "Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human beta cells against proinflammatory insults" @default.
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• W4313365525 doi "https://doi.org/10.1101/2022.12.27.522037" @default.
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