In vivo deficiency of both C/EBPβ and C/EBPε results in highly defective myeloid differentiation and lack of cytokine response.
In vivo deficiency of both C/EBPβ and C/EBPε results in highly defective myeloid differentiation and lack of cytokine response.
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DOI：
10.1371/journal.pone.0015419
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发表时间：
2010-11-03
期刊：
影响因子：
3.7
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Akagi T;Thoennissen NH;George A;Crooks G;Song JH;Okamoto R;Nowak D;Gombart AF;Koeffler HP
CCAAT/增强子结合蛋白（C/EBP）是参与造血细胞发育和诱导几种炎症介质的转录因子。在这里，我们产生了C/EBPβ和C/EBPε双敲除（bbee）小鼠，并将其表型与单缺陷（bbEE和BBee）和野生型（BBEE）小鼠的表型进行了比较。bbee小鼠对致命感染高度敏感，并在2-3个月内死亡。从形态学上看，它们的中性粒细胞在中粒细胞/晚幼粒细胞阶段被阻断，骨髓细胞的克隆形成试验表明bbee小鼠的髓样集落数量显著减少。此外，bbee小鼠骨髓中的造血祖细胞[Lin（-）Sca 1（+）c-Kit（+）]的比例显著增加，反映了髓样区室的分化缺陷。此外，与单敲除小鼠相比，bbee的LPS和IFNγ激活的骨髓源性巨噬细胞的微阵列表达分析显示，基本免疫应答相关基因和网络的表达降低，包括一些直接的C/EBP靶点，如Marco和Clec 4 e。总的来说，bbee小鼠的表型与bbEE或BBee小鼠不同，这表明两种转录因子对中性粒细胞和巨噬细胞以及先天免疫系统的成熟至关重要，并且可以在单敲除小鼠中至少部分地相互补偿。
The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. Here, we generated C/EBPβ and C/EBPε double-knockout (bbee) mice and compared their phenotypes to those of single deficient (bbEE and BBee) and wild-type (BBEE) mice. The bbee mice were highly susceptible to fatal infections and died within 2–3 months. Morphologically, their neutrophils were blocked at the myelocytes/metamyelocytes stage, and clonogenic assays of bone marrow cells indicated a significant decrease in the number of myeloid colonies of the bbee mice. In addition, the proportion of hematopoietic progenitor cells [Lin(−)Sca1(+)c-Kit(+)] in the bone marrow of the bbee mice was significantly increased, reflecting the defective differentiation of the myeloid compartment. Furthermore, microarray expression analysis of LPS- and IFNγ-activated bone marrow-derived macrophages from bbee compared to single knockout mice revealed decreased expression of essential immune response-related genes and networks, including some direct C/EBP-targets such as Marco and Clec4e. Overall, the phenotype of the bbee mice is distinct from either the bbEE or BBee mice, demonstrating that both transcription factors are crucial for the maturation of neutrophils and macrophages, as well as the innate immune system, and can at least in part compensate for each other in the single knockout mice.
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