Shared and distinct functions of the transcription factors IRF4 and IRF8 in myeloid cell development.
Shared and distinct functions of the transcription factors IRF4 and IRF8 in myeloid cell development.
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DOI：
10.1371/journal.pone.0025812
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Tamura T
中科院分区：
文献类型：
--
作者：
Yamamoto M;Kato T;Hotta C;Nishiyama A;Kurotaki D;Yoshinari M;Takami M;Ichino M;Nakazawa M;Matsuyama T;Kamijo R;Kitagawa S;Ozato K;Tamura T
干扰素调节因子（IRF）8和IRF 4是结构相关的造血细胞特异性转录因子，其协同调节树突状细胞和B细胞的分化。虽然在骨髓细胞中，已知IRF 8调节生长和分化，但对IRF 4的作用知之甚少。在这项研究中，我们发现IRF 4在调节骨髓细胞发育方面具有与IRF 8相似的活性。IRF 4在体外骨髓祖细胞中的异位表达抑制细胞生长，促进巨噬细胞，但阻碍粒细胞分化。我们还表明，IRF 4结合并激活转录通过IRF-Ets复合序列（IECS）。此外，我们证明了Irf 8-/-Irf 4-/-小鼠表现出比Irf 8-/-小鼠更严重的慢性粒细胞白血病（CML）样疾病，涉及以单核细胞/巨噬细胞为代价的粒细胞不成比例的扩增。然而，IRF 4-/-小鼠在骨髓细胞发育中没有表现出明显的异常，可能是因为IRF 4在粒细胞-巨噬细胞祖细胞中的表达水平比IRF 8低得多。我们的研究结果还表明，IRF 8和IRF 4在骨髓细胞中不仅具有共同的活性，而且具有特异性。由于IRF 8和IRF 4基因的表达在CML患者中下调，这些结果可能会增加我们对CML发病机制的理解。
Interferon regulatory factor (IRF) 8 and IRF4 are structurally-related, hematopoietic cell-specific transcription factors that cooperatively regulate the differentiation of dendritic cells and B cells. Whilst in myeloid cells IRF8 is known to modulate growth and differentiation, the role of IRF4 is poorly understood. In this study, we show that IRF4 has activities similar to IRF8 in regulating myeloid cell development. The ectopic expression of IRF4 in myeloid progenitor cells in vitro inhibits cell growth, promotes macrophages, but hinders granulocytic cell differentiation. We also show that IRF4 binds to and activates transcription through the IRF-Ets composite sequence (IECS). Furthermore, we demonstrate that Irf8 -/- Irf4 -/- mice exhibit a more severe chronic myeloid leukemia (CML)-like disease than Irf8 -/- mice, involving a disproportionate expansion of granulocytes at the expense of monocytes/macrophages. Irf4 -/- mice, however, display no obvious abnormality in myeloid cell development, presumably because IRF4 is expressed at a much lower level than IRF8 in granulocyte-macrophage progenitors. Our results also suggest that IRF8 and IRF4 have not only common but also specific activities in myeloid cells. Since the expression of both the IRF8 and IRF4 genes is downregulated in CML patients, these results may add to our understanding of CML pathogenesis.
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影响因子：
20.3
作者：
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通讯作者：
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DOI：
10.1073/pnas.0402139101
发表时间：
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作者：
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