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IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IM...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683996/ https://www.ncbi.nlm.nih.gov/pubmed/26621453 http://dx.doi.org/10.1084/jem.20150542 |
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author | Koliaraki, Vasiliki Pasparakis, Manolis Kollias, George |
author_facet | Koliaraki, Vasiliki Pasparakis, Manolis Kollias, George |
author_sort | Koliaraki, Vasiliki |
collection | PubMed |
description | The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine. |
format | Online Article Text |
id | pubmed-4683996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46839962016-06-14 IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer Koliaraki, Vasiliki Pasparakis, Manolis Kollias, George J Exp Med Research Articles The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine. The Rockefeller University Press 2015-12-14 /pmc/articles/PMC4683996/ /pubmed/26621453 http://dx.doi.org/10.1084/jem.20150542 Text en © 2015 Koliaraki et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Koliaraki, Vasiliki Pasparakis, Manolis Kollias, George IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer |
title | IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer |
title_full | IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer |
title_fullStr | IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer |
title_full_unstemmed | IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer |
title_short | IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer |
title_sort | ikkβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683996/ https://www.ncbi.nlm.nih.gov/pubmed/26621453 http://dx.doi.org/10.1084/jem.20150542 |
work_keys_str_mv | AT koliarakivasiliki ikkbinintestinalmesenchymalcellspromotesinitiationofcolitisassociatedcancer AT pasparakismanolis ikkbinintestinalmesenchymalcellspromotesinitiationofcolitisassociatedcancer AT kolliasgeorge ikkbinintestinalmesenchymalcellspromotesinitiationofcolitisassociatedcancer |