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Corss-talk of signals between immunoreceptors and cytokine receptors for development of allergy

免疫受体和细胞因子受体之间信号的相互对话导致过敏的发生

基本信息

批准号：
14206034
负责人：
GOITSUKA Ryo
金额：
$ 27.21万
依托单位：
Tokyo University of Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14206034/
关键词：
allergy cytokine signal transduction IgE receptor mast cell natural killer cell natural killer T cell tumor メモリー細胞 NK細胞 NKT細胞

项目摘要

Various immune cells including mast cells and NKT cells are involved in allergic diseases. These cells express immunoreceptors that react with immunoglobulin E(IgE) or various antigens, and are activated by signals delivered by the interaction of receptors with their respective ligands. In adddition, cytokines produced by these cells deteriorate allergic inflammation. MIST is a member of SLP-76 family adaptor proteins that are involved in immunoreceptor signal transduction, and is expressed in a variety of cytokine-dependent hematopoietic cell lines of myeloid and lymphoid origin. We have demonstrated in the present study that STAT5 is involved in cytokine-mediated up-regulation of MIST gene expression in mast cells by analyzing transcription regulatory elements of the MIST gene. Furthermore, we have revealed that MIST functions as a positive regulator for high-affinity IgE receptor-mediated mast cell degranulation and cytokine production by using MIST-deficient mice. TCR-mediated IFN-γ and IL-4 production by NKT cells was also positively regulated by MIST. In contrast, MIST appears to act as a negative regulator for NK cell receptor-mediated IFN-γ production. This functional conversion of MIST was regulated by the interaction of MIST with Fgr, an Src family kinase expressed in NK cells but not in NKT cells, indicating MIST as an important molecular switch to control diverse responses in different cell populations. Taken together, MIST serves as a link between immunoreceptor- and cytokine-signaling, and can enhance immunoreceptor-mediated activation of immune cells at the site of allergic reactions where abundant cytokines are accumulated. Thus, suppression of MIST expression and/or function could be a potential target for anti-allergic therapy, since MIST deficiency lower the threshold for receptor-mediated activation of mast cells and NKT cells.

包括肥大细胞和NKT细胞在内的各种免疫细胞参与过敏性疾病。这些细胞表达与免疫球蛋白E（IgE）或各种抗原反应的免疫受体，并通过受体与其各自配体相互作用所传递的信号激活。此外，由这些细胞产生的细胞因子恶化过敏性炎症。MIST是参与免疫受体信号转导的SLP-76家族衔接蛋白的成员，并且在多种髓样和淋巴样来源的精氨酸依赖性造血细胞系中表达。在本研究中，我们通过分析MIST基因的转录调控元件，证明STAT 5参与了肥大细胞中马槟榔介导的MIST基因表达上调。此外，我们已经发现，MIST功能作为高亲和力IgE受体介导的肥大细胞脱粒和细胞因子的生产，通过使用MIST缺陷小鼠的正调节剂。TCR介导的NKT细胞产生IFN-γ和IL-4也受到MIST的正调控。相反，MIST似乎作为NK细胞受体介导的IFN-γ产生的负调节剂。MIST的这种功能转换受MIST与Fgr（一种在NK细胞中表达但在NKT细胞中不表达的Src家族激酶）相互作用的调节，表明MIST是控制不同细胞群体中不同反应的重要分子开关。总之，MIST作为免疫受体和精氨酸信号传导之间的联系，并且可以在积累大量细胞因子的过敏反应部位增强免疫受体介导的免疫细胞活化。因此，MIST表达和/或功能的抑制可能是抗过敏治疗的潜在靶标，因为MIST缺乏降低了肥大细胞和NKT细胞的受体介导的活化的阈值。