Apoptosis signals in autoimmune disease

自身免疫性疾病中的细胞凋亡信号

• 批准号: 13670453
• 负责人: KISHI Hiroyuki
• 金额: $ 2.3万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670453/
• 关键词: apoptosis; T-lymphocyte; T cell receptor; MAP kinase; Bax; mitochondria; microsome; caspase activated DNase; T細胞抗原受容体; 胸腺細胞; p38MAPキナーゼ

It is supposed that the auto-reactive T cells are involved in the development of autoimmune diseases. Auto-reactive T cells are usually eliminated from the host by apoptosis that is induced through TCR-signals in the thymus or in the periphery. Dysfunction of the immune surveillance system leads to appearance of auto-reactive T cells in the periphery. In this study, we investigated the TCR signals that induce apoptosis in thymocytes or T cells to unravel the mechanism of the development of autoimmune diseases. First, we analyzed the role of mitochondria in TCR-induced apoptosis of thymocytes and showed that activated p38 kinase pathway by TCR-stimulation induces translocation of Bax to mitochondria, causing DYm-disruption, and the release of cytochrome c, which finally induces caspase-3-mediated apoptosis in thymocytes. Second, we investigated the localization and the function of caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD), which play a central role in chromatin fragmentation in apoptotic cells, in thymocytes prior or post in vivo TCR-stimulation. We showed that TCR-engagement of thymocytes induced caspase-3-dependent activation of CAD localized not only in cytosol but also in microsome, leading to their translocation to nuclei and the resulting DNA fragmentation in harmony. These results will prompt us to analyze the TCR-induced apoptosis signals in T cells from patients of autoimmune diseases.

推测自身反应性T细胞参与了自身免疫性疾病的发生发展。自身反应性T细胞通常通过胸腺或外周的TCR信号诱导的凋亡而从宿主中消除。免疫监视系统的功能障碍会导致外周出现自体反应性T细胞。在这项研究中，我们研究了诱导胸腺细胞或T细胞凋亡的TCR信号，以揭示自身免疫性疾病发展的机制。首先，我们分析了线粒体在TCR诱导胸腺细胞凋亡中的作用，发现TCR激活的p38激酶通路诱导Bax转位到线粒体，导致DYM破坏，细胞色素c释放，最终诱导caspase-3介导的胸腺细胞凋亡。其次，我们研究了半胱氨酸天冬氨酸酶激活的脱氧核糖核酸酶(CAD)及其抑制物(ICAD)在胸腺细胞TCR刺激前后的定位和功能。我们发现，胸腺细胞的TCR参与诱导了caspase-3依赖的CAD的激活，不仅定位于胞浆，也定位于微体，导致它们移位到细胞核，从而导致DNA的协调断裂。这些结果将促使我们分析TCR诱导的自身免疫性疾病患者T细胞的凋亡信号。

项目成果

Nagata T et al.: "The regulation of DNAse activities in subcellular compartments of activated thymocytes."Immunology. 105. 399-406 (2002)

Nagata T 等人：“活化胸腺细胞亚细胞区室中 DNAse 活性的调节。”免疫学。

Nagata T et al.: "The regulation of DNAse activities in subcellular compartments of activated thyocytes"Immunology. 105. 399-406 (2002)

Nagata T 等人：“活化胸细胞亚细胞区室中 DNAse 活性的调节”免疫学。

Nagata T, et al.: "The regulation of DNAse activities in subcellular compartments of activated thymocytes"Immunology. 105. 399-406 (2002)

Nagata T 等人：“活化胸腺细胞亚细胞区室中 DNA 酶活性的调节”免疫学。

Yoshino T et al.: "Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria-mediated cell death in TCR-and dexamethasone-stimulated thymocytes"European Journal of Immunology. 31. 2702-2708 (2001)

Yoshino T 等人：“TCR 和地塞米松刺激的胸腺细胞中线粒体介导的细胞死亡中 p38 MAP 激酶途径和 Bax 易位的不同参与”《欧洲免疫学杂志》。