Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen
Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen
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DOI：
10.1182/blood-2004-07-2639
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发表时间：
2005-03-01
期刊：
影响因子：
20.3
通讯作者：
Saito, T
中科院分区：
文献类型：
--
作者：
Kohno, M;Yamasaki, S;Saito, T
通过免疫球蛋白E （IgE）和抗原（Ag）在肥大细胞上交联FcERI，引发级联反应，导致抗寄生虫或过敏反应。近年来有报道称，不含抗原的IgE（-Ag）能积极促进肥大细胞的存活。尽管我们已经证明FcRgamma中基于酪氨酸的免疫受体激活基序对IgE（-Ag）诱导的肥大细胞存活至关重要，但其潜在机制仍不清楚。在这里，我们研究了IgE（-Ag）诱导肥大细胞缺乏一些下游分子的存活机制。Lyn和Syk是必不可少的，而Fyn、Gab2和磷酸肌苷3-激酶- akt通路对生存不是至关重要的。FcRgamma（-/-）骨髓肥大细胞（BMMCs）的生存失败通过与ige处理的野生型BMMCs共培养得以挽救，这表明FcRgamma（-/-）骨髓肥大细胞的生存不是直接通过FcRgamma（-/-）信号元件诱导的。我们发现生存主要是由白细胞介素3（IL-3）的大量产生介导的，抗IL-3和IL-3(-/-) BMMCs严重损害了生存。在IL-3(-/-) BMMCs中，IgE对Bcl-xL/Bcl-2的上调作用被消除，而组氨酸脱羧酶的表达则被正常诱导。这些结果表明，IL-3在IgE（-Ag）诱导的肥大细胞存活中起着至关重要的作用，通过信号转导和激活因子诱导Bcl-xL/Bcl-2的自分泌方式发挥作用。我们进一步提出，肥大细胞中IgE（-Ag）介导的基因表达受到至少两种机制的调控：依赖自分泌IL-3和不依赖IL-3。(C) 2005年由美国血液病学会出版。
Cross-linking FcERI on mast cells by immunoglobulin E (IgE) and antigen (Ag) initiates cascades leading to antiparasitic or allergic responses. It was recently reported that IgE without antigen, IgE(-Ag), actively promotes mast cell survival. Although we have demonstrated that the immunoreceptor tyrosine-based activation motif within FcRgamma is essential for IgE(-Ag)-induced mast cell survival, the underlying mechanism remains still unclear. Here, we investigated the mechanism of IgE(-Ag)-induced survival using mast cells lacking several downstream molecules. Lyn and Syk were essential, whereas Fyn, Gab2, and the phosphoinositide 3-kinase-Akt pathway were not critical for survival. Failure of survival in FcRgamma(-/-) bone marrow mast cells (BMMCs) was rescued by coculture with IgE-treated wild-type BMMCs, suggesting that survival is induced not directly through Fcis an element ofRI signals. We found that the survival is predominantly mediated by high production of interleukin 3 (IL-3), evidenced by severe impairment of survival by antiIL-3 and in IL-3(-/-) BMMCs. The up-regulation of Bcl-xL/Bcl-2 by IgE was abrogated in IL-3(-/-) BMMCs, whereas the expression of histidine decarboxylase was normally induced. These results indicate that IL-3 plays a crucial role for IgE(-Ag)-induced mast cell survival, functioning in an autocrine manner by inducing the Bcl-xL/Bcl-2 via signal transducer and activator of transduction 5. We further suggest that IgE(-Ag)-mediated gene expression in mast cells is regulated at least 2 mechanisms: autocrine IL-3 dependent and independent. (C) 2005 by The American Society of Hematology.