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Control of immunological tolerance and its breakdown by cytokine

细胞因子控制免疫耐受及其破坏

基本信息

批准号：
14570277
负责人：
TAKESHITA Toshikazu
金额：
$ 2.24万
依托单位：
SHINSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570277/
关键词：
IL-2 signal transduction MAPK p38 Mkk3 Mkk6 apoptosis MAP kinase STAM

项目摘要

Interleukin-2 (IL-2), which was identified as T cell growth factor, plays a important role of the expansion and maintenance in immune response. IL-2-deficient-mice developed colonic inflamation closely resemblling ulcerative colitis in human. The inflamatory disease is characterized by high number of activated T and B cells and elevated immunoglobulin secretion, suggesting that the disease results from an abnormal immune response to a normal antigenic stimulus. On the other hand, immunosuppressive agents, which suppress the effects of IL-2, usually improve various autoimmune disorders. Therefore dysfunction or unusual activation in IL-2 signal transduction has influence on immunological tolerance directly. In this context, we have investigated the molecular machinery of the T cell growth and growth suppression by IL-2 to elucidate the basal mechanism of autoimmune disease. 1)we have established the screening system for the molecule(s) that involved in IL-2 signal transduction using the TPA-Mat, IL-2 and TPA dependent T cell line. 2)we found that the apoptosis of MT-1β resulted from AICD. 3) Although there was no significant difference in IL-2 dependent T cell proliferation among Mkk3^<-/->,Mkk6^<-/-> and wild type mice, the T cells from Mkk3^<-/-> mice were more resistant to apoptosis induced by IL-2 withdrawal. 4)The loss of Mkk3 and Mkk6 during embryogenesis was lethal before embryonic day E11.5. Major defects in the formation of the placenta, heart and deficiencies in the development of the embryonic vasculature were observed. Especially, the labyrinth and spongiotrophoblast layers were markedly decreased in the mutant compared with the wild type. TNF-α did not stimulate activation of p38 MAPK. UV radiation caused p38 MAPK activation in the cells from Mkk3^<-/-> and Mkk6^<-/-> mice, although the extent of p38 MAPK activation was diminished compared with wild-type cells.

白细胞介素2（IL-2）被鉴定为T细胞生长因子，在免疫反应的扩增和维持中发挥着重要作用。 IL-2 缺陷小鼠出现的结肠炎症与人类溃疡性结肠炎非常相似。这种炎症性疾病的特征是大量活化的 T 细胞和 B 细胞以及免疫球蛋白分泌增加，表明该疾病是由对正常抗原刺激的异常免疫反应引起的。另一方面，抑制 IL-2 作用的免疫抑制剂通常可以改善各种自身免疫性疾病。因此IL-2信号转导的功能障碍或异常激活直接影响免疫耐受。在此背景下，我们研究了 T 细胞生长和 IL-2 生长抑制的分子机制，以阐明自身免疫性疾病的基本机制。 1)我们使用TPA-Mat、IL-2和TPA依赖性T细胞系建立了参与IL-2信号转导的分子的筛选系统。 2)我们发现AICD导致MT-1β凋亡。 3) 尽管Mkk3^-/->、Mkk6^-/->和野生型小鼠的IL-2依赖性T细胞增殖没有显着差异，但Mkk3^</-/->小鼠的T细胞对IL-2撤除诱导的细胞凋亡具有更强的抵抗力。 4)胚胎发生过程中Mkk3和Mkk6的丢失在胚胎日E11.5之前是致命的。观察到胎盘、心脏形成的主要缺陷以及胚胎脉管系统发育的缺陷。特别是，与野生型相比，突变体中的迷路和海绵滋养层显着减少。 TNF-α 不刺激 p38 MAPK 的激活。紫外线辐射导致 Mkk3^-/-> 和 Mkk6^-/-> 小鼠细胞中的 p38 MAPK 激活，尽管与野生型细胞相比，p38 MAPK 激活的程度有所减弱。