RESUMO
Introduction: Type 1 diabetes is characterized by pancreatic islet inflammation and autoimmune-driven pancreatic ß-cell destruction. Interferon-α (IFNα) is a key player in early human type 1 diabetes pathogenesis. IFNα activates the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway, leading to inflammation, HLA class I overexpression, endoplasmic reticulum (ER) stress, and ß-cell apoptosis (in synergy with IL-1ß). As TYK2 inhibition has raised as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect ß-cells from the effects of IFNα and other proinflammatory cytokines (i.e., IFNγ and IL-1ß). Methods: All experiments were performed in the human EndoC-ßH1 ß-cell line. HLA class I expression, inflammation, and ER stress were evaluated by real-time PCR, immunoblotting, and/or immunofluorescence. Apoptosis was assessed by the DNA-binding dyes Hoechst 33342 and propidium iodide or caspase 3/7 activity. The promoter activity was assessed by luciferase assay. Results: Deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 activation and MHC class I hyperexpression, in a dose-dependent manner without affecting ß-cell survival and function. A comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signaling pathway. Deucravacitinib protected ß-cells from the effects of two different combinations of cytokines: IFNα + IL-1ß and IFNγ + IL-1ß. Moreover, this TYK2 inhibitor could partially reduce apoptosis and inflammation in cells pre-treated with IFNα + IL-1ß or IFNγ + IL-1ß. Discussion: Our findings suggest that, by protecting ß-cells against the deleterious effects of proinflammatory cytokines without affecting ß-cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes.