Anderson K L, Smith K A, Pio F, Torbett B E, Maki R A
The Burnham Institute and the Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA.
Blood. 1998 Sep 1;92(5):1576-85.
PU.1 is an ets family transcription factor that is expressed specifically in hematopoietic lineages. Through gene disruption studies in mice we have previously shown that the expression of PU.1 is not essential for early myeloid lineage or neutrophil commitment, but is essential for monocyte/macrophage development. We have also shown that PU.1-null (deficient) neutrophils have neutrophil morphology and express neutrophil-specific markers such as Gr-1 and chloroacetate esterase both in vivo and in vitro. We now demonstrate that although PU.1-null mice develop neutrophils, these cells fail to terminally differentiate as shown by the absence of messages for neutrophil secondary granule components and the absence or deficiency of cellular responses to stimuli that normally invoke neutrophil function. Specifically, PU.1-deficient neutrophils fail to respond to selected chemokines, do not generate superoxide ions, and are ineffective at bacterial uptake and killing. The failure to produce superoxide could, in part, be explained by the absence of the gp91 subunit of nicotinamide adenine dinucleotide phosphate oxidase, as shown by our inability to detect messages for the gp91(phox) gene. Incomplete maturation of PU.1-deficient neutrophils is cell autonomous and persists in cultured PU.1-deficient cells. Our results indicate that PU.1 is not necessary for neutrophil lineage commitment but is essential for normal development, maturation, and function of neutrophils.
PU.1是一种ets家族转录因子，在造血谱系中特异性表达。通过对小鼠的基因敲除研究，我们先前已表明，PU.1的表达对于早期髓系谱系或中性粒细胞的定向分化并非必需，但对于单核细胞/巨噬细胞的发育至关重要。我们还表明，PU.1基因缺失（缺陷）的中性粒细胞具有中性粒细胞形态，并且在体内和体外均表达中性粒细胞特异性标志物，如Gr-1和氯乙酸酯酶。我们现在证明，尽管PU.1基因缺失的小鼠能发育出中性粒细胞，但这些细胞无法终末分化，这表现为缺乏中性粒细胞次级颗粒成分的信使，以及对通常引发中性粒细胞功能的刺激缺乏细胞反应或反应缺陷。具体而言，PU.1缺陷的中性粒细胞对选定的趋化因子无反应，不产生超氧离子，并且在细菌摄取和杀伤方面无效。无法产生超氧离子，部分原因可能是烟酰胺腺嘌呤二核苷酸磷酸氧化酶的gp91亚基缺失，这表现为我们无法检测到gp91(phox)基因的信使。PU.1缺陷的中性粒细胞不完全成熟是细胞自主性的，并且在培养的PU.1缺陷细胞中持续存在。我们的结果表明，PU.1对于中性粒细胞谱系的定向分化并非必需，但对于中性粒细胞的正常发育、成熟和功能至关重要。
