Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

Eri H. Kobayashi (), Takafumi Suzuki, Ryo Funayama, Takeshi Nagashima, Makiko Hayashi, Hiroki Sekine, Nobuyuki Tanaka, Takashi Moriguchi, Hozumi Motohashi, Keiko Nakayama and Masayuki Yamamoto ()
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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
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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11624

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