Cytokine-mediated regulation of iron transport in human monocytic cells
Cytokine-mediated regulation of iron transport in human monocytic cells
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DOI：
10.1182/blood-2002-08-2459
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发表时间：
2003-05-15
期刊：
影响因子：
20.3
通讯作者：
Weiss, G
中科院分区：
文献类型：
--
作者：
Ludwiczek, S;Aigner, E;Weiss, G
在慢性炎症条件下，细胞因子诱导铁运输的转移，导致低铁血症和网状内皮系统内金属的保留。然而，这些铁稳态紊乱的调控途径尚不清楚。我们在细胞因子刺激的人单核细胞系THP-1和U937中研究了转铁蛋白受体（TfR）依赖和独立的铁转运机制。用干扰素- γ (ifn - γ)和脂多糖（LIPS）联合处理细胞可降低TfR mRNA水平、表面表达和铁摄取，而这些作用可被白介素-10 （IL-10）逆转，从而刺激TfR介导的铁获取。ifn - γ和LPS剂量依赖性地增加了二价金属转运蛋白-1（亚铁的跨膜转运蛋白）的细胞表达，并刺激了非转铁蛋白结合铁（NTBI）进入细胞的摄取。同时，ifn - γ和LPS下调铁转运蛋白mRNA的表达，减少单核细胞的铁释放。IL-10预孵育部分抵消了这些影响。我们的研究结果表明，促炎刺激ifn - γ和LPS通过刺激二价金属转运蛋白-1的表达增加NTBI的摄取，并通过下调铁转运蛋白的合成引起单核细胞内金属的保留。相反，抗炎细胞因子IL-10刺激tfr介导的铁摄取进入活化的单核细胞。细胞因子对铁转运的调控是慢性病贫血发病的重要机制，也是治疗干预的重要靶点。
Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)-dependent and -independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-gamma (IFN-gamma) and lipopolysaccharide (LIPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-gamma and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-gamma and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-gamma and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention.