Byrd T F, Horwitz M A
Department of Medicine, School of Medicine, University of California, Los Angeles.
J Clin Invest. 1993 Mar;91(3):969-76. doi: 10.1172/JCI116318.
We have investigated the regulation of key human iron binding proteins in mononuclear phagocytes by IFN gamma and iron transferrin. In a previous study, we demonstrated that IFN gamma downregulates the expression on human monocytes of transferrin receptors, the major source of iron for the cell. In the present study, we show that IFN gamma also downregulates the intracellular concentration of ferritin, the major iron storage protein in the cell. By radioimmunoassay, the mean ferritin content of nonactivated monocytes was 361 +/- 107 fg/monocyte (mean +/- SEM) whereas the mean ferritin content of IFN gamma-activated monocytes was 64 +/- 13 fg/monocyte, an 82% reduction with activation (P < 0.01, t test). Consistent with its downregulating effect on these iron proteins, IFN gamma treatment also results in decreased iron incorporation. IFN gamma-activated monocytes incorporated 33% less iron from 59Fe-transferrin than nonactivated monocytes (P < 0.05, t test). Gel filtration chromatography revealed that incorporated iron is located primarily in ferritin in both nonactivated and IFN gamma-activated monocytes. Ferritin in IFN gamma-activated monocytes is saturated with approximately three times as much 59Fe as ferritin in nonactivated monocytes. We have also explored the effect of iron transferrin on transferrin receptor expression and intracellular ferritin content in human monocytes. We have found that iron transferrin markedly upregulates both transferrin receptor expression and intracellular ferritin content in both nonactivated (2.3- and 1.3-fold, respectively) and IFN gamma-activated (3.4- and 2.9-fold, respectively) monocytes. This study demonstrates that transferrin receptor expression and intracellular ferritin content in human monocytes is unidirectionally and coordinately upregulated by iron transferrin and unidirectionally and coordinately downregulated by IFN gamma.
我们研究了干扰素γ（IFNγ）和转铁蛋白对单核吞噬细胞中关键人类铁结合蛋白的调节作用。在先前的一项研究中，我们证明IFNγ可下调转铁蛋白受体在人类单核细胞上的表达，而转铁蛋白受体是细胞铁的主要来源。在本研究中，我们发现IFNγ还可下调细胞内铁蛋白的浓度，铁蛋白是细胞内主要的铁储存蛋白。通过放射免疫测定法，未激活单核细胞的平均铁蛋白含量为361±107 fg/单核细胞（平均值±标准误），而IFNγ激活的单核细胞的平均铁蛋白含量为64±13 fg/单核细胞，激活后降低了82%（P<0.01，t检验）。与其对这些铁蛋白的下调作用一致，IFNγ处理也导致铁摄取减少。IFNγ激活的单核细胞从59Fe-转铁蛋白中摄取的铁比未激活的单核细胞少33%（P<0.05，t检验）。凝胶过滤色谱显示，在未激活和IFNγ激活的单核细胞中，摄取的铁主要位于铁蛋白中。IFNγ激活的单核细胞中的铁蛋白与未激活单核细胞中的铁蛋白相比，59Fe的饱和度约高三倍。我们还探讨了转铁蛋白对人类单核细胞中转铁蛋白受体表达和细胞内铁蛋白含量的影响。我们发现，转铁蛋白显著上调未激活（分别为2.3倍和1.3倍）和IFNγ激活（分别为3.4倍和2.9倍）单核细胞中转铁蛋白受体的表达和细胞内铁蛋白的含量。本研究表明，人类单核细胞中转铁蛋白受体的表达和细胞内铁蛋白的含量受转铁蛋白单向且协同上调，受IFNγ单向且协同下调。
