Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

被引：1427

作者：

Kobayashi, Eri H. ^{[1
]}

Suzuki, Takafumi ^{[1
]}

Funayama, Ryo ^{[2
]}

Nagashima, Takeshi ^{[2
]}

Hayashi, Makiko ^{[1
]}

Sekine, Hiroki ^{[1
,3
]}

Tanaka, Nobuyuki ^{[4
]}

Moriguchi, Takashi ^{[1
]}

Motohashi, Hozumi ^{[3
]}

Nakayama, Keiko ^{[2
]}

Yamamoto, Masayuki ^{[1
,5
]}

机构：

[1] Tohoku Univ, Dept Med Biochem, Grad Sch Med, Aoba Ku, 2-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan

[2] Tohoku Univ, Div Cell Proliferat, Grad Sch Med, Aoba Ku, 2-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan

[3] Tohoku Univ, Dept Gene Express Regulat, Inst Dev Aging & Canc, Aoba Ku, 4-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan

[4] Miyagi Canc Ctr, Res Inst, Div Canc Biol & Therapeut, 47-1 Aza Nodayama, Natori, Miyagi 9811293, Japan

[5] Tohoku Med Megabank Org, Aoba Ku, 2-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; OXIDATIVE STRESS; ANTIOXIDANT; EXPRESSION; MICE; GENE; ACTIVATION; INDUCTION; CELLS; KEAP1;

D O I：

10.1038/ncomms11624

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-1 beta. 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.

引用

页数：14

共 56 条

[1] Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response [J].