Early divergence of Fcε receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival
Early divergence of Fcε receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival
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DOI：
10.4049/jimmunol.173.7.4317
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Kawakami, T
中科院分区：
文献类型：
--
作者：
Kitaura, J;Xiao, WB;Kawakami, T
肥大细胞在 IgE 依赖性速发型超敏反应中发挥着关键作用。单体 IgE 与其高亲和力受体 (FeepsilonRI) 结合可在小鼠肥大细胞中产生许多生物学结果，包括增加 FeepsilonRI 的表面表达并提高存活率。 IgE 分子在诱导细胞因子产生方面表现出异质性；高细胞因子能 IgE 引起广泛的 FcepsilonRI 聚集，从而有效增强存活和其他激活事件，而低细胞因子能 IgE 的效率较低。在这项研究中，我们证明IgE诱导的受体上调对单价半抗原不敏感，单价半抗原可以阻止IgE诱导的受体聚集，而其他激活事件，如受体内化、脱粒、IL-6产生和存活对单价半抗原敏感。 IgE 诱导的受体上调也很独特，因为它不需要 Src 家族激酶、Syk 或 Btk。相比之下，高细胞因子能 IgE 诱导的受体内化依赖于 Lyn，但不依赖于其他 Src 家族激酶、Syk 或 Btk，而脱粒、IL-6 产生和存活则需要 Syk。 IgE 加抗 IgE 或 IgE 加 Ag 的弱至中度刺激可增强存活率，而脱颗粒和 IL-6 的产生则需要更强的信号。总的来说，IgE 结合的 FcepsilonRI 发出的受体上调和内化信号在受体或受体近端水平与其他生物学结果的信号有所不同。
Mast cells play a critical role in IgE-dependent immediate hypersensitivity. Monomeric IgE binding to its high affinity receptor (FeepsilonRI) results in a number of biological outcomes in mouse mast cells, including increased surface expression of FeepsilonRI and enhanced survival. IgE molecules display heterogeneity in inducing cytokine production; highly cytokinergic IgEs cause extensive FcepsilonRI aggregation, leading to potent enhancement of survival and other activation events, whereas poorly cytokinergic IgEs can do so less efficiently. In this study, we demonstrate that IgE-induced receptor up-regulation is not sensitive to monovalent hapten, which can prevent receptor aggregation induced by IgE, whereas other activation events such as receptor internalization, degranulation, IL-6 production, and survival are sensitive to monovalent hapten. IgE-induced receptor up-regulation is also unique in that no Src family kinases, Syk, or Btk are required for it. By contrast, highly cytokinergic IgE-induced receptor internalization is dependent on Lyn, but not other Src family kinases, Syk, or Btk, whereas degranulation, IL-6 production, and survival require Syk. Weak to moderate stimulation with IgE plus anti-IgE or IgE plus Ag enhances survival, while stronger signals are required for degranulation and IL-6 production. Collectively, signals emanated from IgE-bound FcepsilonRI for receptor up-regulation and internalization are shown to diverge at the receptor or receptor-proximal levels from those for other biological outcomes.