Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages

被引：244

作者：

Harada, Nobuhiko ^{[1
]}

Kanayama, Masaya ^{[2
]}

Maruyama, Atsushi ^{[1
]}

Yoshida, Aruto ^{[2
]}

Tazumi, Kyoko ^{[2
]}

Hosoya, Tomonori ^{[1
]}

Mimura, Junsei ^{[1
]}

Toki, Tsutomu ^{[3
]}

Maher, Jonathan M. ^{[4
]}

Yamamoto, Masayuki ^{[4
]}

Itoh, Ken ^{[1
]}

机构：

[1] Hirosaki Univ, Dept Stress Response Sci, Grad Sch Med, Hirosaki, Aomori 0368562, Japan

[2] Kirin Holdings Co Ltd, Cent Labs Frontier Technol, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan

[3] Hirosaki Univ, Dept Pediat, Grad Sch Med, Hirosaki, Aomori 0368562, Japan

[4] Tohoku Univ, Dept Med Biochem, Grad Sch Med, Aoba Ku, Sendai, Miyagi 9808575, Japan

来源：

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS | 2011年 / 508卷 / 01期

关键词：

Nrf2; Macrophage; Ferroportin; 1; Iron metabolism; Inflammation; TRANSCRIPTION FACTOR NRF2; ANTIOXIDANT RESPONSE ELEMENTS; GENE-EXPRESSION; INFLAMMATORY RESPONSES; FORMERLY NRAMP1; HUMAN MONOCYTES; CHRONIC DISEASE; IN-VIVO; HEME; HEPCIDIN;

D O I：

10.1016/j.abb.2011.02.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Iron is an essential element of hemoglobin, and efficient iron recycling from senescent erythrocytes by splenic macrophages is required for erythrocyte hemoglobin synthesis during erythropoiesis. Ferroportin 1 (Fpn1) is the sole iron exporter in mammals, and it also regulates iron reutilization. In this study, we demonstrated genetically that a redox-sensitive transcription factor, Nrf2, regulates Fpn1 mRNA expression in macrophages. Nrf2 activation by several electrophilic compounds commonly resulted in the upregulation of Fpn1 mRNA in bone marrow-derived and peritoneal macrophages obtained from wildtype mice but not from Nrf2 knockout mice. Further, Nrf2 activation enhanced iron release from the J774.1 murine macrophage cell line. Previous studies showed that inflammatory stimuli, such as LPS, downregulates macrophage Fpn1 by transcriptional and hepcidin-mediated post-translational mechanisms leading to iron sequestration by macrophages. We showed that two Nrf2 activators, diethyl maleate and sulforaphane (SFN; a natural Nrf2 activator found in broccoli), restored the LPS-induced suppression of Fpn1 mRNA in human and mouse macrophages, respectively. Furthermore, SFN counteracted the LPS-induced increase of Hepcidin mRNA by an Nrf2-independent mechanism in mouse peritoneal macrophages. These results demonstrate that Nrf2 regulates iron efflux from macrophages through Fpn1 gene transcription and suggest that Nrf2 may control iron metabolism during inflammation. (C) 2011 Elsevier Inc. All rights reserved.

引用

页码：101 / 109

页数：9

共 55 条

[1]

Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages [J].