INTERFERON GAMMA-ACTIVATED HUMAN-MONOCYTES DOWNREGULATE TRANSFERRIN RECEPTORS AND INHIBIT THE INTRACELLULAR MULTIPLICATION OF LEGIONELLA-PNEUMOPHILA BY LIMITING THE AVAILABILITY OF IRON
INTERFERON GAMMA-ACTIVATED HUMAN-MONOCYTES DOWNREGULATE TRANSFERRIN RECEPTORS AND INHIBIT THE INTRACELLULAR MULTIPLICATION OF LEGIONELLA-PNEUMOPHILA BY LIMITING THE AVAILABILITY OF IRON
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DOI：
10.1172/jci114038
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发表时间：
1989-05-01
影响因子：
15.9
通讯作者：
HORWITZ, MA
中科院分区：
文献类型：
--
作者：
BYRD, TF;HORWITZ, MA
我们研究了铁在人单核细胞嗜肺军团菌细胞内生物学中的作用，以及在细胞免疫防御这种细胞内细菌病原体的效应臂中的作用。为了确定嗜肺乳杆菌的细胞内增殖是否依赖于铁，我们研究了铁络合剂去铁胺对单核细胞感染嗜肺乳杆菌的影响。15微米去铁胺可完全抑制嗜肺乳杆菌的细胞内增殖。去铁胺的抑制作用可被等摩尔铁饱和转铁蛋白逆转，但不能逆转载脂蛋白的作用。为了研究铁在单核细胞激活中的潜在作用，我们研究了铁饱和的转铁蛋白对嗜肺乳杆菌在IFN-γ激活的单核细胞中增殖的影响。铁转铁蛋白，而不是载脂蛋白，中和了激活的单核细胞抑制嗜肺乳杆菌增殖的能力。为了探讨激活的单核细胞限制细胞内铁的利用的可能机制，我们检测了体外培养5d的未激活和激活的单核细胞的转铁蛋白受体的表达，通过荧光激活的流式细胞术，激活的单核细胞表达的转铁蛋白受体明显少于未激活的单核细胞。通过Scatchard分析~(125)I-转铁蛋白与单核细胞的结合，未激活的单核细胞有38,300。+-。12,700(平均值+-Se)转铁蛋白结合部位，而激活的单核细胞有10,300.+-。一千六百人，减少百分之七十三。激活的和未激活的单核细胞的平均Kd相似(1.8.+-)。0.2 NM)。这项研究表明：(A)嗜肺乳杆菌的细胞内增殖是铁依赖的；(B)激活的单核细胞通过限制细胞内铁的可获得性来抑制嗜肺乳杆菌的增殖；以及(C)转铁蛋白受体在IFN激活的单核细胞上下调。
We have investigated the role of iron in the intracellular biology of Legionella pneumophila in human monocytes and in the effector arm of cell-mediated immune defense against this intracellular bacterial pathogen. To determine if L. pneumophila intracellular multiplication is iron dependent, we studied the effect of the iron chelator deferoxamine on L. pneumophila infection of monocytes. Deferoxamine at 15 .mu.M completely inhibited L. pneumophila intracellular multiplication. The inhibitory effect of deferoxamine was reversed with equimolar iron-saturated transferrin but not apotransferrin. To examine the potential role of iron in monocyte activation, we investigated the influence of iron-saturated transferrin on L. pneumophila multiplication in IFN.gamma.-activated monocytes. Iron transferrin, but not apotransferrin, neutralized the capacity of activated monocytes to inhibit L. pneumophila multiplication. To explore a potential mechanism by which activated monocytes might limit the availability of intracellular iron, we examined transferrin receptor expression on nonactivated and activated monocytes cultured in vitro for 5 d. By fluorescence-activated flow cytometry, activated monocytes exhibited markedly fewer transferrin receptors than nonactivated monocytes. By Scatchard analysis of 125I-transferrin binding to monocytes, nonactivated monocytes had 38,300 .+-. 12,700 (mean .+-. SE) transferrin bindings site, whereas activated monocytes had 10,300 .+-. 1,600, a reduction of 73%. Activated and nonactivated monocytes had a similar mean Kd (1.8 .+-. 0.2 nM). This study demonstrates that (a) L. pneumophila intracellular multiplication is iron dependent; (b) activated monocytes inhibit L. pneumophila multiplication by limiting the availability of intracellular iron; and (c) transferrin receptors are downregulated on IFN.gamma.-activated monocytes.