Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages
Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages
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DOI：
10.1016/j.abb.2011.02.001
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发表时间：
2011-04-01
影响因子：
3.9
通讯作者：
Itoh, Ken
中科院分区：
文献类型：
--
作者：
Harada, Nobuhiko;Kanayama, Masaya;Itoh, Ken
铁是血红蛋白的必需元素，并且脾巨噬细胞从衰老的红细胞有效地回收铁是红细胞生成期间红细胞血红蛋白合成所需的。转运铁蛋白1（Fpn 1）是哺乳动物体内唯一的铁输出蛋白，同时也调节铁的再利用。在这项研究中，我们从遗传学上证明了氧化还原敏感的转录因子Nrf 2调节巨噬细胞中Fpn 1 mRNA的表达。Nrf 2激活几种亲电子化合物通常导致Fpn 1 mRNA的上调骨髓来源的和从野生型小鼠获得的腹腔巨噬细胞，但不是从Nrf 2敲除小鼠。此外，Nrf 2活化增强了J774.1鼠巨噬细胞系的铁释放。以往的研究表明，炎症刺激，如LPS，下调巨噬细胞Fpn 1的转录和铁调素介导的翻译后机制，导致铁螯合的巨噬细胞。我们发现，两种Nrf 2激活剂，马来酸二乙酯和萝卜硫素（SFN;一种在花椰菜中发现的天然Nrf 2激活剂），分别恢复了LPS诱导的人和小鼠巨噬细胞中Fpn 1 mRNA的抑制。此外，SFN抵消了LPS诱导的增加Hepcidin mRNA的Nrf 2非依赖性机制在小鼠腹腔巨噬细胞。这些结果表明，Nrf 2通过Fpn 1基因转录调节巨噬细胞的铁流出，并表明Nrf 2可能控制炎症过程中的铁代谢。(C)2011 Elsevier Inc. All rights reserved.
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.