Twist-2 controls myeloid lineage development and function.
Twist-2 controls myeloid lineage development and function.
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DOI：
10.1371/journal.pbio.0060316
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发表时间：
2008-12-16
期刊：
影响因子：
9.8
通讯作者：
Chen, Si-Yi
中科院分区：
文献类型：
--
作者：
Sharabi, Andrew B.;Aldrich, Melissa;Sosic, Drazen;Olson, Eric N.;Friedman, Alan D.;Lee, Sung-Hyung;Chen, Si-Yi
碱性螺旋-环-螺旋 (bHLH) 转录因子在淋巴和红细胞发育中发挥关键作用；然而，人们对它们在骨髓谱系发育中的作用知之甚少。在这项研究中，我们确定 bHLH 转录因子 Twist-2 是骨髓谱系发育的关键负调节因子，Twist-2 缺陷小鼠中成熟的骨髓巨噬细胞、中性粒细胞和嗜碱性粒细胞群体的显着增加就表明了这一点。机制研究表明，Twist-2 通过与转录因子 Runx1 和 C/EBPα 相互作用并对其进行抑制，从而抑制粒细胞巨噬细胞祖细胞 (GMP) 的增殖和分化。此外，Twist-2被发现对细胞因子的产生具有相反的作用：抑制促炎细胞因子如白细胞介素12（IL-12）和干扰素-γ（IFNγ）的产生，同时促进骨髓细胞产生调节性细胞因子IL-10。进一步分析的数据表明，Twist-2 激活转录因子 c-Maf，导致 IL-10 表达。此外，Twist-2被发现对于内毒素耐受至关重要。因此，这项研究揭示了 Twist-2 在调节骨髓谱系发育以及成熟骨髓细胞的功能和炎症反应中的关键作用。造血由调节增殖、分化和细胞命运决定的转录因子协调。骨髓生成是指所有白细胞的发育，不包括淋巴细胞（B 和 T 细胞）；然而，这一发育过程的分子调控仍不完全清楚。在这项使用缺乏 Twist-2 表达的小鼠的研究中，我们确定了这种基本螺旋-环-螺旋转录因子作为骨髓祖细胞和完全分化的骨髓细胞调节剂的新作用。具体来说，Twist-2 通过抑制重要的转录因子 Runx1 和 C/EBPα 来抑制祖细胞的增殖和分化，从而产生巨噬细胞、中性粒细胞和嗜碱性粒细胞。在成熟的骨髓细胞中，Twist-2 负向调节促炎细胞因子的产生，同时正向促进这些细胞产生调节性细胞因子 IL-10。这些发现为骨髓谱系发育和功能的调节提供了重要的见解。转录因子Twist-2是一种新的调节因子，可抑制粒细胞巨噬细胞祖细胞的增殖和分化。 Twist-2 还抑制促炎细胞因子的产生，同时刺激骨髓细胞产生 IL-10。
Basic helix-loop-helix (bHLH) transcription factors play critical roles in lymphoid and erythroid development; however, little is known about their role in myeloid lineage development. In this study, we identify the bHLH transcription factor Twist-2 as a key negative regulator of myeloid lineage development, as manifested by marked increases in mature myeloid populations of macrophages, neutrophils, and basophils in Twist-2–deficient mice. Mechanistic studies demonstrate that Twist-2 inhibits the proliferation as well as differentiation of granulocyte macrophage progenitors (GMP) by interacting with and inhibiting the transcription factors Runx1 and C/EBPα. Moreover, Twist-2 was found to have a contrasting effect on cytokine production: inhibiting the production of proinflammatory cytokines such as interleukin-12 (IL-12) and interferon-γ (IFNγ) while promoting the regulatory cytokine IL-10 by myeloid cells. The data from further analyses suggest that Twist-2 activates the transcription factor c-Maf, leading to IL-10 expression. In addition, Twist-2 was found to be essential for endotoxin tolerance. Thus, this study reveals the critical role of Twist-2 in regulating the development of myeloid lineages, as well as the function and inflammatory responses of mature myeloid cells. Hematopoiesis is coordinated by transcription factors that regulate proliferation, differentiation, and cell fate determinations. Myelopoiesis refers to the development of all white blood cells, excluding lymphocytes (B and T cells); however, the molecular regulation of this developmental process is still incompletely understood. In this study using mice that lack expression of Twist-2, we establish a novel role for this basic helix-loop-helix transcription factor as regulator of myeloid progenitors and fully differentiated myeloid cells. Specifically, Twist-2 acts to inhibit proliferation as well as differentiation of progenitors that give rise to macrophages, neutrophils, and basophils by inhibiting the important transcription factors Runx1 and C/EBPα. In mature myeloid cells, Twist-2 negatively regulates the production of proinflammatory cytokines while positively promoting the production of regulatory cytokine IL-10 by these cells. These findings provide significant insight into regulation of myeloid lineage development and function. The transcription factor Twist-2 is a new regulator that inhibits the proliferation and differentiation of granulocyte macrophage progenitors. Twist-2 also inhibits proinflammatory cytokine production, while stimulating IL-10 by myeloid cells.
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影响因子：
11.8
作者：
Bialek, P;Kern, B;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
--
作者：
Carver, EA;Oram, KF;Gridley, T
通讯作者：
Gridley, T
影响因子：
82.9
作者：
Ichikawa, M;Asai, T;Kurokawa, M
通讯作者：
Kurokawa, M
DOI：
10.1073/pnas.091537598
发表时间：
2001-04-24
影响因子：
11.1
作者：
Ikawa, T;Fujimoto, S;Yokota, Y
通讯作者：
Yokota, Y
影响因子：
10.5
作者：
Cripps, RM;Black, BL;Olson, EN
通讯作者：
Olson, EN