Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression
Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression
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DOI：
10.1016/j.bcp.2011.03.030
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发表时间：
2011-07-15
影响因子：
5.8
通讯作者：
Diederich, Marc
中科院分区：
文献类型：
--
作者：
Grigorakaki, Christine;Morceau, Franck;Diederich, Marc
许多生理上的干扰都会导致贫血。在癌症患者中，免疫系统的激活导致包括肿瘤坏死因子α(TNFα)在内的促炎细胞因子的产生，这些细胞因子已被证明通过鲜为人知的机制抑制红细胞的产生。重组人促红细胞生成素(EPO)治疗贫血具有诱导肿瘤生长的作用。本研究旨在探讨肿瘤坏死因子α抑制红细胞生成的机制。从人脐血中分离出CD34(+)造血干/祖细胞。体外红细胞生成是通过EPO刺激细胞来实现的。通过May-Grunwald/Giemsa染色、流式细胞仪分析和荧光显微镜观察，我们发现TNFa明显影响红系的发育。经肿瘤坏死因子α治疗后，HSPC的血红蛋白生成细胞数量以及GATA-1靶基因(EPO受体、血糖蛋白A和珠蛋白)的表达减少。相关地，肿瘤坏死因子α诱导转录因子GATA-2和PU.1的表达，这两种转录因子被描述为红细胞生成的抑制物。在这方面，TNFa促进了GATA-1/PU.1复合体的形成，据报道，该复合体可以阻断GATA-1的转录活性。我们的结果清楚地表明，作为一个早期事件，TNFa通过直接影响红系细胞发育来阻止EPO介导的HSPC的红细胞生成。(C)2011 Elsevier Inc.保留所有权利。
Many physiological perturbations can cause anemia. In cancer patients, activation of the immune system leads to the production of proinflammatory cytokines including tumor necrosis factor alpha (TNF alpha), that have been shown to inhibit red-cell production via poorly understood mechanisms. Treatment of anemia by human recombinant erythropoietin (EPO) is strongly suspected to induce tumor growth. This study focuses on the mechanisms involved in TNF alpha-mediated inhibition of erythropoiesis. CD34(+) hematopoietic stem/progenitor cells (HSPCs) were isolated from human cord blood. Erythropoiesis was achieved in vitro by stimulating cells with EPO. We show that TNFa clearly affected erythroid development, as assessed by May-Grunwald/Giemsa staining, flow cytometry analysis and fluorescent microscopy. The amount of hemoglobin-producing cells as well as the expression of GATA-1 target erythro-specific genes (EPO receptor, glycophorin A and globins) was found decreased after TNF alpha treatment of HSPC. In correlation, TNF alpha induced the expression of the transcription factors GATA-2 and PU.1, described as inhibitors of erythropoiesis. In this regard, TNFa promoted the formation of the GATA-1/PU.1 complex that has been reported to block the transcriptional activity of GATA-1. Our results clearly demonstrate that TNFa prevents EPO-mediated erythropoiesis of HSPC as an early event, by directly affecting erythroid cell development. (C) 2011 Elsevier Inc. All rights reserved.