Affiliation:
1. Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
Abstract
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.
Subject
Endocrinology,Molecular Biology
Reference44 articles.
1. Type 1 diabetes: interferons and the aftermath of pancreatic beta-cell enteroviral infection;Akhbari,2020
2. Enterovirus persistence as a mechanism in the pathogenesis of type 1 diabetes;Alidjinou,2014
3. Characterization of stimulus-secretion coupling in the human pancreatic EndoC-betaH1 beta cell line;Andersson,2015
4. New insights into the role of autoreactive CD8 T cells and cytokines in human type 1 diabetes;Bender,2020
5. Combinatorial association and abundance of components of interferon-stimulated gene factor 3 dictate the selectivity of interferon responses;Bluyssen,1995
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