Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upr...

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Autores principales: Kobayashi, Eri H., Suzuki, Takafumi, Funayama, Ryo, Nagashima, Takeshi, Hayashi, Makiko, Sekine, Hiroki, Tanaka, Nobuyuki, Moriguchi, Takashi, Motohashi, Hozumi, Nakayama, Keiko, Yamamoto, Masayuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879264/
https://www.ncbi.nlm.nih.gov/pubmed/27211851
http://dx.doi.org/10.1038/ncomms11624
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author Kobayashi, Eri H.
Suzuki, Takafumi
Funayama, Ryo
Nagashima, Takeshi
Hayashi, Makiko
Sekine, Hiroki
Tanaka, Nobuyuki
Moriguchi, Takashi
Motohashi, Hozumi
Nakayama, Keiko
Yamamoto, Masayuki
author_facet Kobayashi, Eri H.
Suzuki, Takafumi
Funayama, Ryo
Nagashima, Takeshi
Hayashi, Makiko
Sekine, Hiroki
Tanaka, Nobuyuki
Moriguchi, Takashi
Motohashi, Hozumi
Nakayama, Keiko
Yamamoto, Masayuki
author_sort Kobayashi, Eri H.
collection PubMed
description Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach.
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spelling pubmed-48792642016-06-02 Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription Kobayashi, Eri H. Suzuki, Takafumi Funayama, Ryo Nagashima, Takeshi Hayashi, Makiko Sekine, Hiroki Tanaka, Nobuyuki Moriguchi, Takashi Motohashi, Hozumi Nakayama, Keiko Yamamoto, Masayuki Nat Commun Article Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Nature Publishing Group 2016-05-23 /pmc/articles/PMC4879264/ /pubmed/27211851 http://dx.doi.org/10.1038/ncomms11624 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Kobayashi, Eri H.
Suzuki, Takafumi
Funayama, Ryo
Nagashima, Takeshi
Hayashi, Makiko
Sekine, Hiroki
Tanaka, Nobuyuki
Moriguchi, Takashi
Motohashi, Hozumi
Nakayama, Keiko
Yamamoto, Masayuki
Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
title Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
title_full Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
title_fullStr Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
title_full_unstemmed Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
title_short Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
title_sort nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879264/
https://www.ncbi.nlm.nih.gov/pubmed/27211851
http://dx.doi.org/10.1038/ncomms11624
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