Induction of Bim limits cytokine-mediated prolonged survival of neutrophils
Induction of Bim limits cytokine-mediated prolonged survival of neutrophils
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DOI：
10.1038/cdd.2009.50
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发表时间：
2009-09-01
影响因子：
12.4
通讯作者：
Simon, H. U.
中科院分区：
文献类型：
--
作者：
Andina, N.;Conus, S.;Simon, H. U.
在炎症条件下，中性粒细胞凋亡由于存活因子暴露而延迟，这是一种阻止炎症消退的机制。参与调节中性粒细胞存活/活化的一种重要的促炎细胞因子是粒细胞-巨噬细胞集落刺激因子（GM-CSF）。虽然GM-CSF介导中性粒细胞的抗凋亡作用，但它不能阻止凋亡，并且存活作用是时间依赖性的和有限的。在这里，我们确定了促凋亡Bcl-2家族成员Bim作为一个重要的寿命限制分子在中性粒细胞，特别是在生存因子暴露的条件下。引人注目的是，GM-CSF诱导人和小鼠中性粒细胞中的Bim表达，其被磷脂酰肌醇-3激酶（PI 3 K）的药理学抑制所阻断。在人未成熟骨髓嗜中性粒细胞以及败血性休克患者的血液嗜中性粒细胞中也观察到Bim表达增加;已知这两种细胞群在体内条件下暴露于GM-CSF。在存在和不存在存活细胞因子白细胞介素（IL）-3和GM-CSF的情况下，使用Bim缺陷小鼠中性粒细胞研究Bim的功能作用。缺乏Bim表达导致存活细胞因子阻断中性粒细胞凋亡的功效高得多。总之，这些数据表明Bim在调节中性粒细胞凋亡中的功能作用，并表明GM-CSF和其他中性粒细胞造血素启动了涉及Bim上调的促凋亡反调节。Cell Death and Differentiation（2009）16，1248-1255; doi：10.1038/cdd.2009.50; 2009年5月1日在线发表
Under inflammatory conditions, neutrophil apoptosis is delayed due to survival-factor exposure, a mechanism that prevents the resolution of inflammation. One important proinflammatory cytokine involved in the regulation of neutrophil survival/activation is granulocyte-macrophage colony-stimulating factor (GM-CSF). Although GM-CSF mediates antiapoptotic effects in neutrophils, it does not prevent apoptosis, and the survival effect is both time dependent and limited. Here, we identified the proapoptotic Bcl-2 family member Bim as an important lifespan limiting molecule in neutrophils, particularly under conditions of survival factor exposure. Strikingly, GM-CSF induced Bim expression in both human and mouse neutrophils that was blocked by pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). Increased Bim expression was also seen in human immature bone marrow neutrophils as well as in blood neutrophils from septic shock patients; both cell populations are known to be exposed to GM-CSF under in vivo conditions. The functional role of Bim was investigated using Bim-deficient mouse neutrophils in the presence and absence of the survival cytokines interleukin (IL)-3 and GM-CSF. Lack of Bim expression resulted in a much higher efficacy of the survival cytokines to block neutrophil apoptosis. Taken together, these data demonstrate a functional role for Bim in the regulation of neutrophil apoptosis and suggest that GM-CSF and other neutrophil hematopoietins initiate a proapoptotic counterregulation that involves upregulation of Bim. Cell Death and Differentiation (2009) 16, 1248-1255; doi: 10.1038/cdd.2009.50; published online 1 May 2009