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Temporal regulation of interferon signalling in human EndoC-βH1 cells
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Bioscientifica Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175560/ https://www.ncbi.nlm.nih.gov/pubmed/35521765 http://dx.doi.org/10.1530/JME-21-0224 |
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author | Dhayal, Shalinee Leslie, Kaiyven Afi Baity, Mohammad Akhbari, Pouria Richardson, Sarah J Russell, Mark A Morgan, Noel G |
author_facet | Dhayal, Shalinee Leslie, Kaiyven Afi Baity, Mohammad Akhbari, Pouria Richardson, Sarah J Russell, Mark A Morgan, Noel G |
author_sort | Dhayal, Shalinee |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9175560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Bioscientifica Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-91755602022-06-14 Temporal regulation of interferon signalling in human EndoC-βH1 cells Dhayal, Shalinee Leslie, Kaiyven Afi Baity, Mohammad Akhbari, Pouria Richardson, Sarah J Russell, Mark A Morgan, Noel G J Mol Endocrinol Research 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. Bioscientifica Ltd 2022-04-19 /pmc/articles/PMC9175560/ /pubmed/35521765 http://dx.doi.org/10.1530/JME-21-0224 Text en © The authors https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License. (https://creativecommons.org/licenses/by/4.0/) |
spellingShingle | Research Dhayal, Shalinee Leslie, Kaiyven Afi Baity, Mohammad Akhbari, Pouria Richardson, Sarah J Russell, Mark A Morgan, Noel G Temporal regulation of interferon signalling in human EndoC-βH1 cells |
title | Temporal regulation of interferon signalling in human EndoC-βH1 cells |
title_full | Temporal regulation of interferon signalling in human EndoC-βH1 cells |
title_fullStr | Temporal regulation of interferon signalling in human EndoC-βH1 cells |
title_full_unstemmed | Temporal regulation of interferon signalling in human EndoC-βH1 cells |
title_short | Temporal regulation of interferon signalling in human EndoC-βH1 cells |
title_sort | temporal regulation of interferon signalling in human endoc-βh1 cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175560/ https://www.ncbi.nlm.nih.gov/pubmed/35521765 http://dx.doi.org/10.1530/JME-21-0224 |
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