التفاصيل البيبلوغرافية
| العنوان: |
Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human EndoC-βH1 β-cells against proinflammatory insults |
| المؤلفون: |
Dos Santos, Reinaldo S., Guzman-Llorens, Daniel, Perez-Serna, Atenea A., Nadal, Angel, Marroqui, Laura |
| المصدر: |
Frontiers in Immunology ; volume 14 ; ISSN 1664-3224 |
| بيانات النشر: |
Frontiers Media SA |
| سنة النشر: |
2023 |
| المجموعة: |
Frontiers (Publisher - via CrossRef) |
| مصطلحات موضوعية: |
Immunology, Immunology and Allergy |
| الوصف: |
Introduction Type 1 diabetes is characterized by pancreatic islet inflammation and autoimmune-driven pancreatic β-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 β-cell apoptosis (in synergy with IL-1β). 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 β-cells from the effects of IFNα and other proinflammatory cytokines (i.e., IFNγ and IL-1β). Methods All experiments were performed in the human EndoC-βH1 β-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 β-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 β-cells from the effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially reduce apoptosis and inflammation in cells pre-treated with IFNα + IL-1β or IFNγ + IL-1β. Discussion Our findings suggest that, by protecting β-cells against the deleterious effects of proinflammatory cytokines without affecting β-cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
unknown |
| DOI: |
10.3389/fimmu.2023.1263926 |
| DOI: |
10.3389/fimmu.2023.1263926/full |
| الإتاحة: |
https://doi.org/10.3389/fimmu.2023.1263926Test |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: |
edsbas.3726CEF9 |
| قاعدة البيانات: |
BASE |
