Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California Los Angeles School of Medicine, Los Angeles, California, United States of America.
PLoS One. 2010 Nov 3;5(11):e15419. doi: 10.1371/journal.pone.0015419.
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.
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，我们生成了 C/EBPβ 和 C/EBPε 双敲除（bbee）小鼠，并将其表型与单缺失（bbEE 和 BBee）和野生型（BBee）小鼠进行了比较。bbee 小鼠极易受到致命感染的影响，在 2-3 个月内死亡。形态上，它们的中性粒细胞在骨髓细胞/成髓细胞阶段受阻，骨髓细胞的集落形成实验表明 bbee 小鼠的髓样集落数量显著减少。此外，bbee 小鼠骨髓中造血祖细胞[Lin(-)Sca1(+)c-Kit(+)]的比例显著增加，反映了髓系细胞分化缺陷。此外，与单敲除小鼠相比，LPS 和 IFNγ 激活的 bbee 骨髓来源巨噬细胞的微阵列表达分析显示，与免疫反应相关的重要基因和网络的表达减少，包括一些直接的 C/EBP 靶基因，如 Marco 和 Clec4e。总体而言，bbee 小鼠的表型与 bbEE 或 BBee 小鼠不同，表明这两种转录因子对于中性粒细胞和巨噬细胞的成熟以及先天免疫系统都是至关重要的，并且至少在一定程度上可以在单敲除小鼠中相互补偿。
