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Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation
BACKGROUND AND AIM: Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influe...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839862/ https://www.ncbi.nlm.nih.gov/pubmed/31703091 http://dx.doi.org/10.1371/journal.pone.0225066 |
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author | Kubota, Minori Kakimoto, Kazuki Nakagawa, Takatoshi Koubayashi, Eiko Nakazawa, Kei Tawa, Hideki Hirata, Yuki Okada, Toshihiko Kawakami, Ken Asai, Akira Hosomi, Shuhei Takeuchi, Toshihisa Fukunishi, Shinya Inoue, Takuya Asahi, Michio Higuchi, Kazuhide |
author_facet | Kubota, Minori Kakimoto, Kazuki Nakagawa, Takatoshi Koubayashi, Eiko Nakazawa, Kei Tawa, Hideki Hirata, Yuki Okada, Toshihiko Kawakami, Ken Asai, Akira Hosomi, Shuhei Takeuchi, Toshihisa Fukunishi, Shinya Inoue, Takuya Asahi, Michio Higuchi, Kazuhide |
author_sort | Kubota, Minori |
collection | PubMed |
description | BACKGROUND AND AIM: Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influence of autophagy in IECs on gastrointestinal tract inflammation. METHODS: Mice with conditional knockout of Atg5 in IECs (Atg5(flox/flox)/villin-Cre mice) were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility. Additionally, we used Atg5-silenced rat IECs (IEC6shAtg5 cells) for in vitro assays. RESULTS: Sensitivity to DSS markedly increased in Atg5(flox/flox)/villin-Cre mice compared to that in wild-type mice. In IEC6shAtg5 cells, apoptosis was enhanced, and cell viability significantly decreased compared to IEC-6 cells. The expression of proinflammatory cytokines increased upon suppression of autophagy. Furthermore, silencing of Atg5 was associated with inflammation of IECs, activation of the mitogen-activated protein kinase (MAPK) signaling pathway by the intracellular reactive oxygen species accumulation, and NF-κB p65 phosphorylation. CONCLUSIONS: Autophagy in IECs plays an essential role in the maintenance of intestinal homeostasis, and autophagy deficiency triggers inflammation. Development of methods targeting autophagy might be beneficial in the treatment of IBD. |
format | Online Article Text |
id | pubmed-6839862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-68398622019-11-15 Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation Kubota, Minori Kakimoto, Kazuki Nakagawa, Takatoshi Koubayashi, Eiko Nakazawa, Kei Tawa, Hideki Hirata, Yuki Okada, Toshihiko Kawakami, Ken Asai, Akira Hosomi, Shuhei Takeuchi, Toshihisa Fukunishi, Shinya Inoue, Takuya Asahi, Michio Higuchi, Kazuhide PLoS One Research Article BACKGROUND AND AIM: Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influence of autophagy in IECs on gastrointestinal tract inflammation. METHODS: Mice with conditional knockout of Atg5 in IECs (Atg5(flox/flox)/villin-Cre mice) were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility. Additionally, we used Atg5-silenced rat IECs (IEC6shAtg5 cells) for in vitro assays. RESULTS: Sensitivity to DSS markedly increased in Atg5(flox/flox)/villin-Cre mice compared to that in wild-type mice. In IEC6shAtg5 cells, apoptosis was enhanced, and cell viability significantly decreased compared to IEC-6 cells. The expression of proinflammatory cytokines increased upon suppression of autophagy. Furthermore, silencing of Atg5 was associated with inflammation of IECs, activation of the mitogen-activated protein kinase (MAPK) signaling pathway by the intracellular reactive oxygen species accumulation, and NF-κB p65 phosphorylation. CONCLUSIONS: Autophagy in IECs plays an essential role in the maintenance of intestinal homeostasis, and autophagy deficiency triggers inflammation. Development of methods targeting autophagy might be beneficial in the treatment of IBD. Public Library of Science 2019-11-08 /pmc/articles/PMC6839862/ /pubmed/31703091 http://dx.doi.org/10.1371/journal.pone.0225066 Text en © 2019 Kubota 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Kubota, Minori Kakimoto, Kazuki Nakagawa, Takatoshi Koubayashi, Eiko Nakazawa, Kei Tawa, Hideki Hirata, Yuki Okada, Toshihiko Kawakami, Ken Asai, Akira Hosomi, Shuhei Takeuchi, Toshihisa Fukunishi, Shinya Inoue, Takuya Asahi, Michio Higuchi, Kazuhide Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation |
title | Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation |
title_full | Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation |
title_fullStr | Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation |
title_full_unstemmed | Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation |
title_short | Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation |
title_sort | autophagy deficiency exacerbates colitis through excessive oxidative stress and mapk signaling pathway activation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839862/ https://www.ncbi.nlm.nih.gov/pubmed/31703091 http://dx.doi.org/10.1371/journal.pone.0225066 |
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