Laboratory of Cellular and Molecular Physiology, GIGA-Research, University of Liège, Liège, Belgium.
PLoS One. 2007 Aug 15;2(8):e727. doi: 10.1371/journal.pone.0000727.
Although STAT5 promotes survival of hematopoietic progenitors, STAT5-/- mice develop mild neutrophilia.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that in STAT5-/- mice, liver endothelial cells (LECs) autonomously secrete high amounts of G-CSF, allowing myeloid progenitors to overcompensate for their intrinsic survival defect. However, when injected with pro-inflammatory cytokines, mutant mice cannot further increase neutrophil production, display a severe deficiency in peripheral neutrophil survival, and are therefore unable to maintain neutrophil homeostasis. In wild-type mice, inflammatory stimulation induces rapid STAT5 degradation in LECs, G-CSF production by LECs and other cell types, and then sustained mobilization and expansion of long-lived neutrophils.
We conclude that STAT5 is an ambivalent factor. In cells of the granulocytic lineage, it exerts an antiapoptotic function that is required for maintenance of neutrophil homeostasis, especially during the inflammatory response. In LECs, STAT5 negatively regulates granulopoiesis by directly or indirectly repressing G-CSF expression. Removal of this STAT5-imposed brake contributes to induction of emergency granulopoiesis.
尽管 STAT5 促进造血祖细胞的存活，但 STAT5-/- 小鼠仍会出现轻度中性粒细胞增多。
方法/主要发现：在这里，我们表明在 STAT5-/- 小鼠中，肝内皮细胞（LEC）自主分泌大量 G-CSF，使髓系祖细胞能够过度补偿其内在的生存缺陷。然而，当注射促炎细胞因子时，突变小鼠不能进一步增加中性粒细胞的产生，外周中性粒细胞的存活严重缺乏，因此无法维持中性粒细胞的动态平衡。在野生型小鼠中，炎症刺激诱导 LEC 中 STAT5 的快速降解、LEC 和其他细胞类型产生 G-CSF，然后是长寿命中性粒细胞的快速动员和扩增。
我们得出结论，STAT5 是一个矛盾的因素。在粒细胞谱系细胞中，它发挥抗凋亡功能，这是维持中性粒细胞动态平衡所必需的，特别是在炎症反应期间。在 LEC 中，STAT5 通过直接或间接抑制 G-CSF 的表达来负调控粒细胞生成。消除这种 STAT5 施加的制动有助于诱导紧急粒细胞生成。
