IL-3 Maintains Activation of the p90S6K/RPS6 Pathway and Increases Translation in Human Eosinophils.
IL-3 Maintains Activation of the p90S6K/RPS6 Pathway and Increases Translation in Human Eosinophils.
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DOI：
10.4049/jimmunol.1500871
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发表时间：
2015-09-15
期刊：
影响因子：
--
通讯作者：
Jarjour NN
中科院分区：
文献类型：
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作者：
Esnault S;Kelly EA;Shen ZJ;Johansson MW;Malter JS;Jarjour NN
IL-5 是减少嗜酸性粒细胞增多的主要治疗靶点。然而，所有嗜酸性粒细胞激活细胞因子 IL-5、IL-3 和 GM-CSF 通常都存在于包括过敏性哮喘在内的特应性疾病中。由于这 3 种细胞因子在嗜酸性粒细胞上的功能冗余以及气道嗜酸性粒细胞上 IL-5 受体的缺失，因此考虑 IL-3 和 GM-CSF 对于有效降低组织嗜酸性粒细胞功能非常重要。此外，这 3 种细胞因子通过共同的 β 链受体发出信号，但对嗜酸性粒细胞中蛋白质的产生有不同的影响。值得注意的是，IL-3 在不影响 mRNA 水平的情况下诱导 semaphorin-7A 等蛋白质产生的能力增强，表明 IL-3 对翻译具有独特的影响。本研究的目的是确定与 IL-5 和 GM-CSF 相比，IL-3 独特影响嗜酸性粒细胞功能的机制，重点是蛋白质翻译。外周血嗜酸性粒细胞用于研究用 IL-3、GM-CSF 或 IL-5 激活的细胞中的细胞内信号传导和蛋白质翻译。我们确定，与 GM-CSF 或 IL-5 不同，IL-3 通过激活核糖体蛋白 (RP) S6 和上游激酶 p90S6K 来触发延长的信号传导。阻断 p90S6K 激活可抑制 RPS6 的磷酸化和 IL-3 增强的 semaphorin-7A 翻译。此外，在过敏原挑战的环境中，与循环嗜酸性粒细胞相比，人呼吸道中 RPS6 和 p90S6K 的体内磷酸化增强。我们的研究结果为 IL-3、GM-CSF 和 IL-5 差异激活嗜酸性粒细胞的机制提供了新的见解。这些观察结果将 IL-3 及其下游细胞内信号视为调节嗜酸性粒细胞功能的新靶标。
IL-5 is a major therapeutic target to reduce eosinophilia. However, all of the eosinophil-activating cytokines IL-5, IL-3, and GM-CSF are typically present in atopic diseases including allergic asthma. Due to the functional redundancy of these 3 cytokines on eosinophils and the loss of IL-5 receptor on airway eosinophils, it is important to take IL-3 and GM-CSF into account to efficiently reduce tissue eosinophil functions. Moreover, these 3 cytokines signal through a common β-chain receptor, and yet differentially affect protein production in eosinophils. Notably, the increased ability of IL-3 to induce production of proteins such as semaphorin-7A without affecting mRNA level suggests a unique influence by IL-3 on translation. The purpose of this study is to identify the mechanisms by which IL-3 distinctively affects eosinophil function compared to IL-5 and GM-CSF, with a focus on protein translation. Peripheral blood eosinophils were used to study intracellular signaling and protein translation in cells activated with IL-3, GM-CSF or IL-5. We establish that, unlike GM-CSF or IL-5, IL-3 triggers prolonged signaling through activation of ribosomal protein (RP) S6 and the upstream kinase, p90S6K. Blockade of p90S6K activation inhibited phosphorylation of RPS6 and IL-3-enhanced semaphorin-7A translation. Furthermore, in an allergen-challenged environment, in vivo phosphorylation of RPS6 and p90S6K was enhanced in human airway compared to circulating eosinophils. Our findings provide new insights into the mechanisms underlying differential activation of eosinophils by IL-3, GM-CSF, and IL-5. These observations place IL-3 and its downstream intracellular signals as novel targets that should be considered to modulate eosinophil functions.