IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with β-catenin relocalization
IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with β-catenin relocalization
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DOI：
10.1189/jlb.1105636
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发表时间：
2006-07-01
影响因子：
5.5
通讯作者：
Coffer, Paul J.
中科院分区：
文献类型：
--
作者：
Rosas, Marcela;Dijkers, Pascale F.;Coffer, Paul J.
白细胞介素 (IL)-5 是一种造血细胞因子，能够调节嗜酸性粒细胞的分化、存活和效应功能。它与其受体特异性结合，该受体由细胞因子特异性 α 链和与 IL-3 和粒细胞巨噬细胞集落刺激因子受体共享的 β 链组成。 IL-5 调节嗜酸性粒细胞存活的分子机制仍不清楚。在这项研究中，我们证明 IL-5 的撤除可通过线粒体依赖性途径诱导嗜酸性粒细胞凋亡，与 Fas 受体激活无关。脂质激酶磷脂酰肌醇 3 激酶在维持嗜酸性粒细胞存活中发挥着至关重要的作用，因为抑制其活性会导致细胞凋亡。 IL-5 诱导磷酸化，从而抑制 Forkhead 转录因子 FOXO3a 和糖原合成酶激酶 3 (GSK-3)。我们分析了 FOXO3a 依赖性转录靶标：Fas 配体或 Bim（促凋亡 Bcl-2 家族成员）的表达，但在凋亡嗜酸性粒细胞中均未检测到。我们进一步表明，GSK-3 在 IL-5 撤除后被激活，抑制其活性可挽救嗜酸性粒细胞免于凋亡。 β-连环蛋白是 GSK-3 的直接底物，存在于 IL-5 刺激的嗜酸性粒细胞的细胞核中，但在缺乏细胞因子的情况下，它以 GSK-3 依赖性方式转位至质膜。这是第一份描述 GSK-3 和 β-连环蛋白在调节嗜酸性粒细胞存活中的潜在作用的报告，并提出了 IL-5 抑制这些细胞中组成性凋亡程序的新机制。
Interleukin (IL)-5 is a hematopoietic cytokine able to regulate differentiation, survival, and effector functions of eosinophils. It binds specifically to its receptor, which is composed of a cytokine-specific alpha-chain and a beta-chain shared with the receptors for IL-3 and the granulocyte macrophage-colony stimulating factor. The molecular mechanisms by which IL-5 modulates eosinophil survival remain unclear. In this study, we demonstrate that IL-5 withdrawal induces eosinophil apoptosis through a mitochondria-dependent pathway, independently of Fas receptor activation. The lipid kinase phosphatidylinositol-3 kinase plays a crucial role in the maintenance of eosinophil survival, as inhibition of its activity results in apoptosis. IL-5 induces phosphorylation and thus, inhibition of the Forkhead transcription factor FOXO3a and glycogen synthase kinase 3 (GSK-3). We analyzed expression of FOXO3a-dependent transcriptional targets: Fas ligand or Bim (a proapoptotic Bcl-2 family member), but neither was detected in apoptotic eosinophils. We further show that GSK-3 is activated after IL-5 withdrawal, and inhibition of its activity rescues eosinophils from apoptosis. beta-catenin, a direct GSK-3 substrate, is present in the nucleus of IL-5-stimulated eosinophils, but it is translocated to the plasma membrane in the absence of cytokine in a GSK-3-dependent manner. This is the first report describing a potential role for GSK-3 and beta-catenin in regulating eosinophil survival and suggests a novel mechanism by which IL-5 inhibits the constitutive apoptotic program in these cells.