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MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury
Intestinal ischemia/reperfusion (I/R) injury causes inflammation and tissue damage and is associated with high morbidity and mortality. Uncontrolled activation of the innate immune system through toll-like receptors (Tlr) plays a key role in I/R-mediated tissue damage but the underlying mechanisms h...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
WILEY-VCH Verlag
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531605/ https://www.ncbi.nlm.nih.gov/pubmed/23143987 http://dx.doi.org/10.1002/emmm.201201298 |
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author | Chassin, Cécilia Hempel, Cordelia Stockinger, Silvia Dupont, Aline Kübler, Joachim F Wedemeyer, Jochen Vandewalle, Alain Hornef, Mathias W |
author_facet | Chassin, Cécilia Hempel, Cordelia Stockinger, Silvia Dupont, Aline Kübler, Joachim F Wedemeyer, Jochen Vandewalle, Alain Hornef, Mathias W |
author_sort | Chassin, Cécilia |
collection | PubMed |
description | Intestinal ischemia/reperfusion (I/R) injury causes inflammation and tissue damage and is associated with high morbidity and mortality. Uncontrolled activation of the innate immune system through toll-like receptors (Tlr) plays a key role in I/R-mediated tissue damage but the underlying mechanisms have not been fully resolved. Here, we identify post-transcriptional upregulation of the essential Tlr signalling molecule interleukin 1 receptor-associated kinase (Irak) 1 as the causative mechanism for post-ischemic immune hyper-responsiveness of intestinal epithelial cells. Increased Irak1 protein levels enhanced epithelial ligand responsiveness, chemokine secretion, apoptosis and mucosal barrier disruption in an experimental intestinal I/R model using wild-type, Irak1(−/−) and Tlr4(−/−) mice and ischemic human intestinal tissue. Irak1 accumulation under hypoxic conditions was associated with reduced K48 ubiquitination and enhanced Senp1-mediated deSUMOylation of Irak1. Importantly, administration of microRNA (miR)-146a or induction of miR-146a by the phytochemical diindolylmethane controlled Irak1 upregulation and prevented immune hyper-responsiveness in mouse and human tissue. These findings indicate that Irak1 accumulation triggers I/R-induced epithelial immune hyper-responsiveness and suggest that the induction of miR-146a offers a promising strategy to prevent I/R tissue injury. |
format | Online Article Text |
id | pubmed-3531605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | WILEY-VCH Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-35316052013-01-04 MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury Chassin, Cécilia Hempel, Cordelia Stockinger, Silvia Dupont, Aline Kübler, Joachim F Wedemeyer, Jochen Vandewalle, Alain Hornef, Mathias W EMBO Mol Med Research Articles Intestinal ischemia/reperfusion (I/R) injury causes inflammation and tissue damage and is associated with high morbidity and mortality. Uncontrolled activation of the innate immune system through toll-like receptors (Tlr) plays a key role in I/R-mediated tissue damage but the underlying mechanisms have not been fully resolved. Here, we identify post-transcriptional upregulation of the essential Tlr signalling molecule interleukin 1 receptor-associated kinase (Irak) 1 as the causative mechanism for post-ischemic immune hyper-responsiveness of intestinal epithelial cells. Increased Irak1 protein levels enhanced epithelial ligand responsiveness, chemokine secretion, apoptosis and mucosal barrier disruption in an experimental intestinal I/R model using wild-type, Irak1(−/−) and Tlr4(−/−) mice and ischemic human intestinal tissue. Irak1 accumulation under hypoxic conditions was associated with reduced K48 ubiquitination and enhanced Senp1-mediated deSUMOylation of Irak1. Importantly, administration of microRNA (miR)-146a or induction of miR-146a by the phytochemical diindolylmethane controlled Irak1 upregulation and prevented immune hyper-responsiveness in mouse and human tissue. These findings indicate that Irak1 accumulation triggers I/R-induced epithelial immune hyper-responsiveness and suggest that the induction of miR-146a offers a promising strategy to prevent I/R tissue injury. WILEY-VCH Verlag 2012-12 2012-11-09 /pmc/articles/PMC3531605/ /pubmed/23143987 http://dx.doi.org/10.1002/emmm.201201298 Text en Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Research Articles Chassin, Cécilia Hempel, Cordelia Stockinger, Silvia Dupont, Aline Kübler, Joachim F Wedemeyer, Jochen Vandewalle, Alain Hornef, Mathias W MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury |
title | MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury |
title_full | MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury |
title_fullStr | MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury |
title_full_unstemmed | MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury |
title_short | MicroRNA-146a-mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury |
title_sort | microrna-146a-mediated downregulation of irak1 protects mouse and human small intestine against ischemia/reperfusion injury |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531605/ https://www.ncbi.nlm.nih.gov/pubmed/23143987 http://dx.doi.org/10.1002/emmm.201201298 |
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