Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
PLoS One. 2011;6(10):e25812. doi: 10.1371/journal.pone.0025812. Epub 2011 Oct 7.
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.
干扰素调节因子 (IRF) 8 和 IRF4 是结构相关的、造血细胞特异性转录因子，它们协同调节树突状细胞和 B 细胞的分化。虽然在髓样细胞中，IRF8 已知调节生长和分化，但 IRF4 的作用知之甚少。在这项研究中，我们表明 IRF4 具有与 IRF8 相似的调节髓样细胞发育的活性。IRF4 在体外髓样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，IRF4 通过 IRF-Ets 复合序列 (IECS) 结合并激活转录。此外，我们证明 Irf8⁻/⁻Irf4⁻/⁻小鼠表现出比 Irf8⁻/⁻小鼠更严重的慢性髓性白血病 (CML) 样疾病，涉及粒细胞的不成比例扩张，而单核细胞/巨噬细胞减少。然而，Irf4⁻/⁻小鼠在髓样细胞发育中没有明显异常，可能是因为 IRF4 在粒细胞-巨噬细胞祖细胞中的表达水平远低于 IRF8。我们的结果还表明，IRF8 和 IRF4 在髓样细胞中不仅具有共同的作用，而且具有特定的作用。由于 CML 患者的 IRF8 和 IRF4 基因表达均下调，这些结果可能有助于我们理解 CML 的发病机制。
