SOCS3 is a physiological negative regulator for granulopoiesis and granulocyte colony-stimulating factor receptor signaling
SOCS3 is a physiological negative regulator for granulopoiesis and granulocyte colony-stimulating factor receptor signaling
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DOI：
10.1074/jbc.c300496200
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发表时间：
2004-02-20
影响因子：
4.8
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
--
作者：
Kimura, A;Kinjyo, I;Yoshimura, A
细胞因子信号传导抑制因子 3 (SOCS3/CIS3) 已被证明是细胞因子的重要负调节因子，尤其是激活 STAT3 的细胞因子。为了研究SOCS3在体内中性粒细胞和粒细胞集落刺激因子（G-CSF）信号传导中的作用，我们比较了两种类型的条件敲除小鼠的中性粒细胞，即LysM-Cre：SOCS3（fl/fl）小鼠和Tie2-Cre：SOCS3（fl/fl）小鼠，其中成熟中性粒细胞和造血干细胞中的Socs3基因已分别被删除。来自 Tie2-Cre:SOCS3(fl/fl) 小鼠骨髓的 G-CSF 依赖性集落的大小比来自对照野生型小鼠的集落大得多，而白细胞介素 3 依赖性集落的大小相似。此外，LysM-Cre:SOCS3(fl/fl) 小鼠比 SOCS3(fl/fl) 小鼠具有更多的中性粒细胞，表明 SOCS3 是中性粒细胞中 G-CSF 信号传导的负调节因子。与这一观点一致，在 SOCS3 缺陷的成熟中性粒细胞中，G-CSF 诱导的 STAT3 以及丝裂原激活的蛋白激酶激活比野生型中性粒细胞中的激活更强且时间更长。 G-CSF 对细胞凋亡的预防作用在 SOCS3 缺陷的成熟中性粒细胞中比对照中性粒细胞更显着。这些数据表明 SOCS3 负向调节中性粒细胞中的粒细胞生成和 G-CSF 信号传导，并可能导致中性粒细胞增多或中性粒细胞减少。
The suppressor of cytokine signaling-3 (SOCS3/CIS3) has been shown to be an important negative regulator of cytokines, especially cytokines that activate STAT3. To examine the role of SOCS3 in neutrophils and the granulocyte colony-stimulating factor (G-CSF) signaling in vivo, we compared neutrophils from two types of conditional knockout mice, LysM-Cre:SOCS3(fl/fl) mice and Tie2-Cre:SOCS3(fl/fl) mice, in which the Socs3 gene had been deleted in mature neutrophils and hematopoietic stem cells, respectively. The size of the G-CSF-dependent colonies from Tie2-Cre:SOCS3(fl/fl) mouse bone marrow was much larger than that of colonies from control wild-type mice, while the size of interleukin-3-dependent colonies was similar. Moreover, LysM-Cre:SOCS3(fl/fl) mice had more neutrophils than SOCS3(fl/fl) mice, suggesting that SOCS3 is a negative regulator of G-CSF signaling in neutrophils. Consistent with this notion, G-CSF-induced STAT3 as well as mitogen-activated protein kinase activation was much stronger and prolonged in SOCS3-deficient mature neutrophils than in wildtype neutrophils. The preventive effect of G-CSF on apoptosis was more prominent in SOCS3-deficient mature neutrophils than in control neutrophils. These data indicate that SOCS3 negatively regulates granulopoiesis and G-CSF signaling in neutrophils and may contribute to neutrophilia or neutropenia.