title: Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription.
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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Eri H
authors.initials: EH
authors.lastname: Kobayashi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Cell Proliferation, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.affiliation: Division of Cell Proliferation, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.|Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sekine
authors.affiliation: Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.affiliation: Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Hozumi
authors.identifier: http://orcid.org/0000-0002-7261-1033
authors.initials: H
authors.lastname: Motohashi
authors.affiliation: Division of Cell Proliferation, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.|Tohoku Medical-Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D012319:RNA Polymerase II / Q000378:metabolism
chemical_list: D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012319:RNA Polymerase II