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IL-2缺陷小鼠产生的结肠炎症中发挥着重要作用，该炎症与人类的溃疡性结肠炎非常相似。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，这表明该疾病是由于对正常抗原刺激的异常免疫反应引起的。 IL-2 的作用通常会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会直接影响免疫耐受。在此背景下，我们研究了 T 细胞生长和生长抑制的分子机制。 IL-2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MT-1β的凋亡是由AICD引起的。3)尽管Mkk3^<-/->、Mkk6^</-/->和野生型之间IL-2依赖性T细胞增殖没有显着差异。小鼠中，来自 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 的丢失在胚胎日之前是致命的。 E11.5.与野生型相比，在突变体中观察到胎盘、心脏形成的主要缺陷和胚胎脉管系统的发育缺陷。刺激 p38 MAPK 的激活 UV 辐射导致 Mkk3^<-/-> 和 Mkk6^<-/-> 小鼠细胞中的 p38 MAPK 激活，尽管程度不同。与野生型细胞相比，p38 MAPK 激活减弱。