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Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

Author

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  • Eri H. Kobayashi

    (Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku)

  • Takafumi Suzuki

    (Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku)

  • Ryo Funayama

    (Tohoku University Graduate School of Medicine)

  • Takeshi Nagashima

    (Tohoku University Graduate School of Medicine)

  • Makiko Hayashi

    (Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku)

  • Hiroki Sekine

    (Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku
    Institute of Development, Aging and Cancer, Tohoku University)

  • Nobuyuki Tanaka

    (Miyagi Cancer Center Research Institute)

  • Takashi Moriguchi

    (Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku)

  • Hozumi Motohashi

    (Institute of Development, Aging and Cancer, Tohoku University)

  • Keiko Nakayama

    (Tohoku University Graduate School of Medicine)

  • Masayuki Yamamoto

    (Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku
    Tohoku Medical-Megabank Organization)

Abstract

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.

Suggested Citation

  • Eri H. Kobayashi & Takafumi Suzuki & Ryo Funayama & Takeshi Nagashima & Makiko Hayashi & Hiroki Sekine & Nobuyuki Tanaka & Takashi Moriguchi & Hozumi Motohashi & Keiko Nakayama & Masayuki Yamamoto, 2016. "Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11624
    DOI: 10.1038/ncomms11624
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    Cited by:

    1. Gaozan Tong & Yiming Chen & Xixi Chen & Junfu Fan & Kunxuan Zhu & ZiJing Hu & Santie Li & Junjie Zhu & Jianjun Feng & Zhaohang Wu & Zhenyu Hu & Bin Zhou & Litai Jin & Hui Chen & Jingling Shen & Weitao, 2023. "FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Qian Xiao & Joseph Mears & Aparna Nathan & Kazuyoshi Ishigaki & Yuriy Baglaenko & Noha Lim & Laura A. Cooney & Kristina M. Harris & Mark S. Anderson & David A. Fox & Dawn E. Smilek & James G. Krueger , 2023. "Immunosuppression causes dynamic changes in expression QTLs in psoriatic skin," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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