Loss of Hepatocyte-Nuclear-Factor-4α Affects Colonic Ion Transport and Causes Chronic Inflammation Resembling Inflammatory Bowel Disease in Mice
| Autor: | Emile Levy, Elena F. Verdu, Jean-Philippe Babeu, Andrée-Anne Dupuis, Ernest G. Seidman, Fernand-Pierre Gendron, François Boudreau, Mathieu Darsigny, Emma E. Furth |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
endocrine system
Chemokine Transcription Genetic Colon Cell Biology/Cell Growth and Division lcsh:Medicine Inflammation Mice Transgenic digestive system Inflammatory bowel disease 03 medical and health sciences Mice 0302 clinical medicine Immune system medicine Animals Homeostasis Colitis Intestinal Mucosa lcsh:Science Cell Biology/Gene Expression 030304 developmental biology Oligonucleotide Array Sequence Analysis 0303 health sciences Multidisciplinary Gastroenterology and Hepatology/Inflammatory Bowel Disease Ion Transport biology lcsh:R Membrane Proteins Cell Biology/Cellular Death and Stress Responses medicine.disease Inflammatory Bowel Diseases 3. Good health Hepatocyte nuclear factors Hepatocyte nuclear factor 4 Hepatocyte Nuclear Factor 4 Immunology Claudins biology.protein lcsh:Q 030211 gastroenterology & hepatology medicine.symptom Gene Deletion Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 4, Iss 10, p e7609 (2009) |
| ISSN: | 1932-6203 |
| Popis: | BACKGROUND Hnf4alpha, 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 Hnf4alpha in the maintenance of gut inflammatory homeostasis in mice. METHODOLOGY/PRINCIPAL FINDINGS We show here that specific epithelial deletion of Hnf4alpha 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 Hnf4alpha 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 Hnf4alpha 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 Hnf4alpha 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 Hnf4alpha to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4alpha in the regulation of claudin-15 expression. This establishes Hnf4alpha as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis. |
| Databáze: | OpenAIRE |
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