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Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice

BACKGROUND: Hnf4α, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim o...

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Autores principales: Darsigny, Mathieu, Babeu, Jean-Philippe, Dupuis, Andrée-Anne, Furth, Emma E., Seidman, Ernest G., Lévy, Émile, Verdu, Elena F., Gendron, Fernand-Pierre, Boudreau, François
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764139/
https://www.ncbi.nlm.nih.gov/pubmed/19898610
http://dx.doi.org/10.1371/journal.pone.0007609
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author Darsigny, Mathieu
Babeu, Jean-Philippe
Dupuis, Andrée-Anne
Furth, Emma E.
Seidman, Ernest G.
Lévy, Émile
Verdu, Elena F.
Gendron, Fernand-Pierre
Boudreau, François
author_facet Darsigny, Mathieu
Babeu, Jean-Philippe
Dupuis, Andrée-Anne
Furth, Emma E.
Seidman, Ernest G.
Lévy, Émile
Verdu, Elena F.
Gendron, Fernand-Pierre
Boudreau, François
author_sort Darsigny, Mathieu
collection PubMed
description BACKGROUND: Hnf4α, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4α in the maintenance of gut inflammatory homeostasis in mice. METHODOLOGY/PRINCIPAL FINDINGS: We show here that specific epithelial deletion of Hnf4α in mice causes spontaneous chronic intestinal inflammation leading to focal areas of crypt dropout, increased cytokines and chemokines secretion, immune cell infiltrates and crypt hyperplasia. A gene profiling analysis in diseased Hnf4α null colon confirms profound genetic changes in cell death and proliferative behaviour related to cancer. Among the genes involved in the immune protection through epithelial barrier function, we identify the ion transporter claudin-15 to be down-modulated early in the colon of Hnf4α mutants. This coincides with a significant decrease of mucosal ion transport but not of barrier permeability in young animals prior to the manifestation of the disease. We confirm that claudin-15 is a direct Hnf4α gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease. CONCLUSION: Our results highlight the critical role of Hnf4α to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4α in the regulation of claudin-15 expression. This establishes Hnf4α as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis.
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spelling pubmed-27641392009-11-06 Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice Darsigny, Mathieu Babeu, Jean-Philippe Dupuis, Andrée-Anne Furth, Emma E. Seidman, Ernest G. Lévy, Émile Verdu, Elena F. Gendron, Fernand-Pierre Boudreau, François PLoS One Research Article BACKGROUND: Hnf4α, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4α in the maintenance of gut inflammatory homeostasis in mice. METHODOLOGY/PRINCIPAL FINDINGS: We show here that specific epithelial deletion of Hnf4α in mice causes spontaneous chronic intestinal inflammation leading to focal areas of crypt dropout, increased cytokines and chemokines secretion, immune cell infiltrates and crypt hyperplasia. A gene profiling analysis in diseased Hnf4α null colon confirms profound genetic changes in cell death and proliferative behaviour related to cancer. Among the genes involved in the immune protection through epithelial barrier function, we identify the ion transporter claudin-15 to be down-modulated early in the colon of Hnf4α mutants. This coincides with a significant decrease of mucosal ion transport but not of barrier permeability in young animals prior to the manifestation of the disease. We confirm that claudin-15 is a direct Hnf4α gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease. CONCLUSION: Our results highlight the critical role of Hnf4α to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4α in the regulation of claudin-15 expression. This establishes Hnf4α as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis. Public Library of Science 2009-10-29 /pmc/articles/PMC2764139/ /pubmed/19898610 http://dx.doi.org/10.1371/journal.pone.0007609 Text en Darsigny et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Darsigny, Mathieu
Babeu, Jean-Philippe
Dupuis, Andrée-Anne
Furth, Emma E.
Seidman, Ernest G.
Lévy, Émile
Verdu, Elena F.
Gendron, Fernand-Pierre
Boudreau, François
Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice
title Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice
title_full Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice
title_fullStr Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice
title_full_unstemmed Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice
title_short Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice
title_sort loss of hepatocyte-nuclear-factor-4α affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764139/
https://www.ncbi.nlm.nih.gov/pubmed/19898610
http://dx.doi.org/10.1371/journal.pone.0007609
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