Homeostatic erythropoiesis by the transcription factor IRF2 through attenuation of type I interferon signaling
Homeostatic erythropoiesis by the transcription factor IRF2 through attenuation of type I interferon signaling
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DOI：
10.1016/j.exphem.2007.11.004
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发表时间：
2008-01-01
影响因子：
2.6
通讯作者：
Honda, Kenya
中科院分区：
文献类型：
--
作者：
Mizutani, Tatsuaki;Tsuji, Kohichiro;Honda, Kenya
客观的。红细胞的产生受到细胞因子的严格调节，特别是促红细胞生成素 (EPO)，它通过诱导多种因子（包括 Bcl2 样 1 (Bcl-XL)）影响红系细胞的扩增和活力。由于已知 I 型干扰素 (IFN) 会抑制红细胞生成，因此我们研究了干扰素调节因子 2 (IRF2) 基因缺陷的小鼠，该基因在红细胞生成调节的背景下充当 I 型 IFN 信号传导的负调节因子。材料和方法。我们进行了血液学分析并检测了 Irj2 缺陷小鼠的正细胞性贫血。结果。通过流式细胞术评估 Irf2 缺陷骨髓中红系祖细胞的成熟情况，发现晚期成红细胞数量减少，同时早期红系祖细胞数量增加。 Irf2缺陷小鼠表现出血清EPO水平升高、Bcl-XL表达水平降低以及成红细胞凋亡增强，这可能是晚期成红细胞数量减少的原因。我们进一步评估了IRF2在红细胞生成过程中I型IFN信号传导调节中的作用，发现I型IFN受体复合物亚基IFNAR1的额外纯合突变可挽救Irf2缺陷小鼠的红细胞生成缺陷。结论。 Irf2 缺陷小鼠的红细胞生成受损是由于 I 型 IFN 信号传导过度所致，该信号传导抑制红系细胞中的 Bcl-XL 表达。我们目前的研究提供了对红细胞生成过程中 I 型 IFN 和 EPO 信号通路之间潜在相互作用的机制理解，并可能为贫血的治疗提供见解。 (c) 2008 年 ISEH - 血液学和干细胞学会。由爱思唯尔公司出版
Objective. Erythrocyte production is tightly regulated by cytokines, particularly erythropoietin (EPO), which affects expansion and viability of erythroid lineage cells via induction of several factors, including Bcl2-like 1 (Bcl-XL). Because type I interferon (IFN) is known to inhibit erythropoiesis, we studied mice deficient in the gene for interferon regulatory factor 2 (IRF2), which functions as a negative regulator of type I IFN signaling, in the context of erythropoiesis regulation.Materials and Methods. We performed hematologic analyses and detected normocytic anemia in Irj2-deficient mice.Results. Assessment of the maturation of erythroid progenitors in Irf2-deficient bone marrow by flow cytometry revealed a decreased number of late erythroblasts accompanied by an increased number of early erythroid progenitors. Irf2-deficient mice manifested elevated serum EPO levels, decreased Bcl-XL expression levels and enhanced apoptosis of erythroblasts, which may account for the decreased number of late erythroblasts. We further assessed the role of IRF2 in the regulation of type I IFN signaling during erythropoiesis, and found that additional homozygous mutation of IFNAR1, a subunit of type I IFN receptor complex, led to rescue of the defect of erythropoiesis in Irf2-deficient mice.Conclusions. Impaired erythropoiesis in Irf2-deficient mice results from excessive type I IFN signaling, which inhibits Bcl-XL expression in erythroid lineage cells. Our present study provides a mechanistic understanding of the potential cross-talk between type I IFN and EPO signaling pathways during erythropoiesis and may offer therapeutic insights into anemia. (c) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.