Nitric oxide-mediated induction of ferritin synthesis in J774 macrophages by inflammatory cytokines: Role of selective iron regulatory protein-2 downregulation
Nitric oxide-mediated induction of ferritin synthesis in J774 macrophages by inflammatory cytokines: Role of selective iron regulatory protein-2 downregulation
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DOI：
10.1182/blood.v91.3.1059.1059_1059_1066
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发表时间：
1998-02-01
期刊：
影响因子：
20.3
通讯作者：
Cairo, G
中科院分区：
文献类型：
--
作者：
Recalcati, S;Taramelli, D;Cairo, G
细胞因子处理的巨噬细胞代表了一个有用的模型，以解开网状内皮细胞（RE）铁潴留在炎症条件下的分子基础。在本研究中，我们表明，刺激小鼠巨噬细胞J774细胞与干扰素（IFN）-γ/脂多糖（LPS）导致一氧化氮依赖性调节铁调节蛋白（IRP）的活性-1和2。细胞质蛋白质，结合RNA基序称为铁反应元件（IRE），控制铁蛋白翻译。用细胞因子刺激引起IRP-1活性的小幅增加和IRP-2活性的强烈降低，伴随着铁蛋白合成和积累的增加。细胞因子诱导的H链铁蛋白mRNA只有轻微增加，从而表明IRP-2介导的转录后调控在控制铁蛋白表达中起着重要作用。这一点通过直接证明IRP的翻译抑制功能在刺激的细胞中受损而得到证实。事实上。在IRE序列控制下的报告转录物在无细胞提取物中的翻译被来自于经精氨酸处理的细胞的含IRP的裂解物抑制的效率低于来自于对照细胞的裂解物。我们的发现揭示了IRP-2的作用，表明：（i）该蛋白以与IRP-1相反的方式响应刺激;（2）当大量表达时，如在J774细胞中，IRP-2足以调节活细胞中的细胞内铁代谢;（3）通过增加铁蛋白的合成，IRP-2可能在炎症过程中调节RE细胞的铁稳态中发挥作用。(C)1998年，美国血液学会。
Cytokine-treated macrophages represent a useful model to unravel the molecular basis of reticuloendothelial (RE) iron retention in inflammatory conditions. In the present study, we showed that stimulation of murine macrophage J774 cells with interferon (IFN)-gamma/lipopalysaccharide (LPS) resulted in a nitric oxide-dependent modulation of the activity of iron regulatory proteins (IRP)-1 and 2. cytoplasmic proteins which, binding to RNA motifs called iron responsive elements (IRE), control ferritin translation. Stimulation with cytokines caused a small increase of IRP-1 activity and a strong reduction of IRP-2 activity accompanied by increased ferritin synthesis and accumulation. Cytokines induced only a minor increase of H chain ferritin mRNA, thus indicating that IRP-2-mediated posttranscriptional regulation plays a major role in the control of ferritin expression. This was confirmed by direct demonstration that the translational repression function of IRP was impaired in stimulated cells. In fact. translation in cell-free extracts of a reporter transcript under the control of an IRE sequence was repressed less efficiently by IRP-containing lysates from cytokine-treated cells than by lysates from control cells. Our findings throw light on the role of IRP-2 showing that: (i) this protein responds to a stimulus in opposite fashion to IRP-1; (2) when abundantly expressed, as in J774 cells, IRP-2 is sufficient to regulate intracellular iron metabolism in living cells; and (3) by allowing increased ferritin synthesis, IRP-2 may play a role in the regulation of iron homeostasis in RE cells during inflammation. (C) 1998 by The American Society of Hematology.