美国麻省理工学院科学家近日通过研究，发现了铁循环的关键蛋白。这一发现将有助于为β-地中海贫血病等遗传血液病提供新的治疗手段。相关论文10月11日在线发表于《临床检查杂志》（Journal of Clinical Investigation）上。
此次研究由麻省理工学院（MIT）哈佛－麻省理工健康科学与技术部（HST）的科学家Jane-Jane Chen领导完成。两年前，她和研究小组发现，一种真核转录起始因子蛋白激酶（HRI）能够使患有β-地中海贫血病的小鼠保持存活。之后研究表明，HRI能够最大化减少球蛋白链反常的、有毒的不稳定性，这对红血球中的血色素来说至关重要。血色素的作用在于将氧输入身体器官并将二氧化碳带走。
在最新的研究中，Chen和研究小组发现，当小鼠体内缺乏HRI时，铁循环就会变慢，结果导致制造红血球的铁离子变少。
研究人员通过进一步的研究揭示了HRI作用于铁循环的深层机制。首先，缺乏HRI会导致另一种蛋白－hepcidin的含量降低，而hepcidin是铁循环的主要调控者，它会释放身体内贮存的铁并使其能够进入血色素，缺乏hepcidin，身体内贮存的铁就无法得到有效利用。
另外，研究人员发现，HRI主要是在巨噬细胞中进行表达。一旦身体缺乏HRI，巨噬细胞就无法发挥正常的功能，也就是无法吞噬“垂死”的红血球并释放出铁，这样一来，红血球死亡后就会通过肾脏排出体外，造成身体铁的净损失。
根据这一发现，Chen目前正和研究小组进行一项新的研究，希望找出能够调控HRI信号路径的分子。“也许我们将发现某种化合物，它能够帮助治疗β-地中海贫血病以及其它HRI起作用的疾病”，她说。（科学时报）
原始出处:
J. Clin. Invest. doi:10.1172/JCI32084.
The function of heme-regulated eIF2 kinase in murine iron homeostasis and macrophage maturation
Sijin Liu1, Rajasekhar N.V.S. Suragani1, Fudi Wang2, Anping Han1, Wanting Zhao1, Nancy C. Andrews2 and Jane-Jane Chen1
1Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 2Division of Hematology/Oncology, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Jane-Jane Chen, E25-545, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. Phone: (617) 253-9674; Fax: (617) 253-3459; E-mail: j-jchen@mit.edu .
Received for publication March 9, 2007, and accepted in revised form July 18, 2007.
Heme-regulated eIF2 kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and ß-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri–/– mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri–/– mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri–/– mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri–/– macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.
