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Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer

In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related c...

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Autores principales: Richter, Cornelia, Herrero San Juan, Martina, Weigmann, Benno, Bergis, Dominik, Dauber, Katrin, Muders, Michael H., Baretton, Gustavo B., Pfeilschifter, Josef Martin, Bonig, Halvard, Brenner, Sebastian, Radeke, Heinfried H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271172/
https://www.ncbi.nlm.nih.gov/pubmed/28191009
http://dx.doi.org/10.3389/fimmu.2017.00044
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author Richter, Cornelia
Herrero San Juan, Martina
Weigmann, Benno
Bergis, Dominik
Dauber, Katrin
Muders, Michael H.
Baretton, Gustavo B.
Pfeilschifter, Josef Martin
Bonig, Halvard
Brenner, Sebastian
Radeke, Heinfried H.
author_facet Richter, Cornelia
Herrero San Juan, Martina
Weigmann, Benno
Bergis, Dominik
Dauber, Katrin
Muders, Michael H.
Baretton, Gustavo B.
Pfeilschifter, Josef Martin
Bonig, Halvard
Brenner, Sebastian
Radeke, Heinfried H.
author_sort Richter, Cornelia
collection PubMed
description In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model. Initially, we found that IL-12−/− mice developed less severe colitis but are highly susceptible to colon cancer. By contrast, p47phox−/− mice showed lower tumor scores and fewer high grade tumors than wild-type (WT) littermates. Treatment with toll-like receptor 9 ligand CpG2216 significantly enhanced colitis in p47phox−/− mice, whereas tumor growth was simultaneously reduced. In tumor tissue of p47phox−/− mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage. Reconstitution of WT mice with IL-23p19−/− bone marrow protected these mice from colon cancer, whereas transplantation of WT hematopoiesis into IL-23p19−/− mice increased the susceptibility to tumor growth. Our study strengthens the divergent role of IL-12 and IL-23 in colon cancer development. With the characterization of p47phox as a novel modulator of both cytokines our investigation introduces a promising new target for antitumor strategies.
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spelling pubmed-52711722017-02-10 Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer Richter, Cornelia Herrero San Juan, Martina Weigmann, Benno Bergis, Dominik Dauber, Katrin Muders, Michael H. Baretton, Gustavo B. Pfeilschifter, Josef Martin Bonig, Halvard Brenner, Sebastian Radeke, Heinfried H. Front Immunol Immunology In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model. Initially, we found that IL-12−/− mice developed less severe colitis but are highly susceptible to colon cancer. By contrast, p47phox−/− mice showed lower tumor scores and fewer high grade tumors than wild-type (WT) littermates. Treatment with toll-like receptor 9 ligand CpG2216 significantly enhanced colitis in p47phox−/− mice, whereas tumor growth was simultaneously reduced. In tumor tissue of p47phox−/− mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage. Reconstitution of WT mice with IL-23p19−/− bone marrow protected these mice from colon cancer, whereas transplantation of WT hematopoiesis into IL-23p19−/− mice increased the susceptibility to tumor growth. Our study strengthens the divergent role of IL-12 and IL-23 in colon cancer development. With the characterization of p47phox as a novel modulator of both cytokines our investigation introduces a promising new target for antitumor strategies. Frontiers Media S.A. 2017-01-27 /pmc/articles/PMC5271172/ /pubmed/28191009 http://dx.doi.org/10.3389/fimmu.2017.00044 Text en Copyright © 2017 Richter, Herrero San Juan, Weigmann, Bergis, Dauber, Muders, Baretton, Pfeilschifter, Bonig, Brenner and Radeke. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Richter, Cornelia
Herrero San Juan, Martina
Weigmann, Benno
Bergis, Dominik
Dauber, Katrin
Muders, Michael H.
Baretton, Gustavo B.
Pfeilschifter, Josef Martin
Bonig, Halvard
Brenner, Sebastian
Radeke, Heinfried H.
Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer
title Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer
title_full Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer
title_fullStr Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer
title_full_unstemmed Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer
title_short Defective IL-23/IL-17 Axis Protects p47phox−/− Mice from Colon Cancer
title_sort defective il-23/il-17 axis protects p47phox−/− mice from colon cancer
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271172/
https://www.ncbi.nlm.nih.gov/pubmed/28191009
http://dx.doi.org/10.3389/fimmu.2017.00044
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