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Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation
Intestinal epithelial cells are adapted in mucosal hypoxia and hypoxia-inducible factors in these cells can fortify barrier integrity to support mucosal tissue healing. Here we investigated whether hypoxia-related pathways could be proposed as potential therapeutic targets for inflammatory bowel dis...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840603/ https://www.ncbi.nlm.nih.gov/pubmed/33519819 http://dx.doi.org/10.3389/fimmu.2020.609689 |
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author | Kim, Young-In Yi, Eun-Je Kim, Young-Dae Lee, A Reum Chung, Jiwoung Ha, Hae Chan Cho, Joong Myung Kim, Seong-Ryeol Ko, Hyun-Jeong Cheon, Jae-Hee Hong, Yong Rae Chang, Sun-Young |
author_facet | Kim, Young-In Yi, Eun-Je Kim, Young-Dae Lee, A Reum Chung, Jiwoung Ha, Hae Chan Cho, Joong Myung Kim, Seong-Ryeol Ko, Hyun-Jeong Cheon, Jae-Hee Hong, Yong Rae Chang, Sun-Young |
author_sort | Kim, Young-In |
collection | PubMed |
description | Intestinal epithelial cells are adapted in mucosal hypoxia and hypoxia-inducible factors in these cells can fortify barrier integrity to support mucosal tissue healing. Here we investigated whether hypoxia-related pathways could be proposed as potential therapeutic targets for inflammatory bowel disease. We developed a novel hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, CG-598 which stabilized HIF-1α in the gut tissue. Treatment of CG-598 did not affect extra-intestinal organs or cause any significant adverse effects such as erythropoiesis. In the experimental murine colitis model, CG-598 ameliorated intestinal inflammation with reduction of inflammatory lesions and pro-inflammatory cytokines. CG-598 treatment fortified barrier function by increasing the expression of intestinal trefoil factor, CD73, E-cadherin and mucin. Also, IL-10 and IL-22 were induced from lamina propria CD4(+) T-cells. The effectiveness of CG-598 was comparable to other immunosuppressive therapeutics such as TNF-blockers or JAK inhibitors. These results suggest that CG-598 could be a promising therapeutic candidate to treat inflammatory bowel disease. |
format | Online Article Text |
id | pubmed-7840603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78406032021-01-29 Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation Kim, Young-In Yi, Eun-Je Kim, Young-Dae Lee, A Reum Chung, Jiwoung Ha, Hae Chan Cho, Joong Myung Kim, Seong-Ryeol Ko, Hyun-Jeong Cheon, Jae-Hee Hong, Yong Rae Chang, Sun-Young Front Immunol Immunology Intestinal epithelial cells are adapted in mucosal hypoxia and hypoxia-inducible factors in these cells can fortify barrier integrity to support mucosal tissue healing. Here we investigated whether hypoxia-related pathways could be proposed as potential therapeutic targets for inflammatory bowel disease. We developed a novel hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, CG-598 which stabilized HIF-1α in the gut tissue. Treatment of CG-598 did not affect extra-intestinal organs or cause any significant adverse effects such as erythropoiesis. In the experimental murine colitis model, CG-598 ameliorated intestinal inflammation with reduction of inflammatory lesions and pro-inflammatory cytokines. CG-598 treatment fortified barrier function by increasing the expression of intestinal trefoil factor, CD73, E-cadherin and mucin. Also, IL-10 and IL-22 were induced from lamina propria CD4(+) T-cells. The effectiveness of CG-598 was comparable to other immunosuppressive therapeutics such as TNF-blockers or JAK inhibitors. These results suggest that CG-598 could be a promising therapeutic candidate to treat inflammatory bowel disease. Frontiers Media S.A. 2021-01-14 /pmc/articles/PMC7840603/ /pubmed/33519819 http://dx.doi.org/10.3389/fimmu.2020.609689 Text en Copyright © 2021 Kim, Yi, Kim, Lee, Chung, Ha, Cho, Kim, Ko, Cheon, Hong and Chang 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) and the copyright owner(s) 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 Kim, Young-In Yi, Eun-Je Kim, Young-Dae Lee, A Reum Chung, Jiwoung Ha, Hae Chan Cho, Joong Myung Kim, Seong-Ryeol Ko, Hyun-Jeong Cheon, Jae-Hee Hong, Yong Rae Chang, Sun-Young Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation |
title | Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation |
title_full | Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation |
title_fullStr | Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation |
title_full_unstemmed | Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation |
title_short | Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation |
title_sort | local stabilization of hypoxia-inducible factor-1α controls intestinal inflammation via enhanced gut barrier function and immune regulation |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840603/ https://www.ncbi.nlm.nih.gov/pubmed/33519819 http://dx.doi.org/10.3389/fimmu.2020.609689 |
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