Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK.
J Mol Endocrinol. 2022 May 19;69(2):299-313. doi: 10.1530/JME-21-0224.
During the development of type 1 diabetes, interferons (IFN) are elaborated from islet-infiltrating immune cells and/or from virally infected β-cells. They act via specific receptors to increase, acutely, the phosphorylation of the transcription factors STAT1 and 2. However, the longer-term impacts of chronic IFN stimulation are poorly understood and were investigated in the current study. Human EndoC-βH1 cells were treated with IFNα, IFNγ or IFNλ either acutely (<2 h) or chronically (≥24 h) and STAT phosphorylation, expression and activity were assessed by Western blotting and transcriptional reporter assays. Exposure of β-cells to IFNα or IFNλ induced a swift increase in the phosphorylation of both STAT1 and STAT2, whereas IFNγ increased only pSTAT1. Over more extended periods (≥24 h), STAT phosphorylation declined but STAT1 and STAT2 expression were enhanced in a sustained manner. All IFNs stimulated ISRE transcriptional activity (but with different time courses), whereas GAS activity was responsive only to IFNγ. The re-addition of a second bolus of IFNα, 24 h after an initial dose, failed to cause renewed STAT1/2 phosphorylation. By contrast, when IFNγ was added 24 h after exposure to IFNα, rapid STAT1 phosphorylation was re-initiated. Exposure of β-cells to IFNs leads to rapid, transient, STAT phosphorylation and to slower and more sustained increases in total STAT1/2 levels. The initial phosphorylation response is accompanied by marked desensitisation to the cognate agonist. Together, the results reveal that the response of β-cells to IFNs is regulated both temporally and quantitatively to achieve effective signal integration.
在 1 型糖尿病的发展过程中，干扰素 (IFN) 由胰岛浸润的免疫细胞和/或病毒感染的 β 细胞产生。它们通过特异性受体作用，急性增加转录因子 STAT1 和 STAT2 的磷酸化。然而，慢性 IFN 刺激的长期影响知之甚少，本研究对此进行了探讨。人 EndoC-βH1 细胞用 IFNα、IFNγ 或 IFNλ 急性（<2 h）或慢性（≥24 h）处理，通过 Western blot 和转录报告基因检测评估 STAT 磷酸化、表达和活性。β 细胞暴露于 IFNα 或 IFNλ 会迅速增加 STAT1 和 STAT2 的磷酸化，而 IFNγ 仅增加 pSTAT1。在更长的时间（≥24 h）内，STAT 磷酸化下降，但 STAT1 和 STAT2 的表达持续增强。所有 IFNs 均刺激 ISRE 转录活性（但时间进程不同），而 GAS 活性仅对 IFNγ 有反应。在初始剂量 24 小时后再次加入第二剂量 IFNα 未能引起 STAT1/2 的再次磷酸化。相比之下，当 IFNγ 在暴露于 IFNα 24 小时后加入时，快速的 STAT1 磷酸化被重新启动。IFN 暴露导致 β 细胞快速、短暂的 STAT 磷酸化，并导致总 STAT1/2 水平的缓慢和更持续增加。初始磷酸化反应伴随着对同源激动剂的明显脱敏。总之，这些结果表明，β 细胞对 IFNs 的反应受到时间和数量的调节，以实现有效的信号整合。
