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Regulation of Immune responses and autoimmune diseases by cytokines

细胞因子对免疫反应和自身免疫性疾病的调节

基本信息

批准号：
15002008
负责人：
HIRANO Toshio
金额：
$ 380.22万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Specially Promoted Research
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15002008/
关键词：
memory T cells cytokine homeostatic proliferation of T cells Zinc intracellular signaling second messenger メモリー T 細胞 T 細胞の恒常的な増殖 IL-6 GP130 STAT3 免疫細胞運動樹状細胞 T細胞 gp130 自己免疫疾患

项目摘要

Our aim of this study was to know how Y759F mutation in gp130, an IL-6 signal transducer, induces an autoimmune arthritis disease in vivo and to investigate a role of IL-6-mediated signaling in the normal immune responses. We obtained two important concepts showing how tissue specific autoimmune diseases are induced as described below.(1) Excess IL-7 expression induced by activation of non-hematopoietic cells via an excess IL-6 signaling triggers an excess homeostatic proliferation of CD4+ T cells followed by the development of autoimmune arthritis in F759 mice. We demonstrated how a dysregulated interaction between non-hematopoietic cells and hematopoietic cells, CD4+ T cells, induces a tissue specific autoimmune diseases in vivo.(2) There is an IL-17-mediated IL-6 positive feedback loop in non-hematopoietic cells even in normal condition in vivo. Dysregulation of the IL-6 loop by a genetic abnormality such as Y759F mutation in F759 mice induces an excess production of IL-6 via the loop followed by the development of autoimmune arthritis.Moreover, we proved the existence of intracellular Zinc signaling, which is also important for regulation of immune cell functions.

本研究的目的是了解IL-6信号转导子gp 130中的Y 759 F突变如何在体内诱导自身免疫性关节炎疾病，并研究IL-6介导的信号转导在正常免疫应答中的作用。我们获得了两个重要的概念，显示了组织特异性自身免疫性疾病是如何诱导的，如下所述。(1)在F759小鼠中，通过过量IL-6信号传导激活非造血细胞诱导的过量IL-7表达触发了CD 4 + T细胞的过度稳态增殖，随后发展为自身免疫性关节炎。我们证明了非造血细胞和造血细胞（CD 4 + T细胞）之间的失调相互作用如何在体内诱导组织特异性自身免疫性疾病。(2)即使在体内正常条件下，在非造血细胞中也存在IL-17介导的IL-6正反馈环。在F759小鼠中，由于遗传异常如Y 759 F突变导致IL-6环的失调，通过该环诱导IL-6的过量产生，随后发展为自身免疫性关节炎。此外，我们证明了细胞内锌信号的存在，其对于免疫细胞功能的调节也是重要的。