Functional analysis of IL-1 in immune and stress responses using gene knockout mice

使用基因敲除小鼠进行 IL-1 在免疫和应激反应中的功能分析

基本信息

批准号：
10670298
负责人：
ASANO Masahide
金额：
$ 0.9万
依托单位：
Kanazawa University (2000-2001)The University of Tokyo (1998-1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

IL-1 α, IL-1 β, IL-Ira KO and IL-1 α/β double KO mice were generated to elucidate pleiotropic function of IL-1 in an animal body, and roles of IL-1 in immune and stress responses were clarified as described below.(1) IL-1 β , but not IL-1 α, is crucial in terpentine-induced fever development and glucocorticoid secretion.(2) Inflammation induced by apoptosis inducer Fas ligand is mediated by IL-1 β which is released by caspase 1 independent mechanism.(3) Chronic inflammatory arthropathy resembling rheumatoid arthritis is spontaneously developed in IL-Ira KO mice on a BALB/c background.(4) LPS-induced HIV-1 expression in transgenic mice is mediated by TNF α and IL-1.(5) In collaboration with other laboratories, apoptosis in neural cells caused by ischaemia and apoptosis in germ cells caused by loss of ataxia telangiectasia-mutated (Atm) gene function are mediated by IL-1β.(6) T cell-dependent antibody production is regulated by IL-1 β, but not by IL-1 α, through induction of CD40L and OX40 on T cells.(7) IL-1α, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity.(8) Suppression of autoimmune arthritis in IL-1 KO mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells.In support with the Grant-in-Aid for Scientific Research, various roles of IL-1 in fever development, stress response, antibody production, contact hypersensitivity, rheumatoid arthritis development and apoptosis of neural cells and germ cells were elucidated. These results and our IL-1 genes KO mice could be very useful to understand the mechanism of IL-1-mediated human diseases and to develop medical treatment for them.

制备IL-1α、IL-1β、IL-Ira KO和IL-1α/β双KO小鼠，以阐明IL-1在动物体内的多效性功能以及IL-1在免疫和应激反应中的作用澄清如下。(1) IL-1β，而不是 IL-1α，在萜烯诱导的发热发展和糖皮质激素分泌中至关重要。(2) 细胞凋亡诱导剂诱导的炎症Fas 配体由 IL-1 β 介导，IL-1 β 通过 caspase 1 独立机制释放。(3) 在 BALB/c 背景下，IL-Ira KO 小鼠自发形成慢性炎症性关节病重组类风湿性关节炎。(4) LPS 诱导的 HIV转基因小鼠中-1的表达是由TNFα和IL-1介导的。(5)与其他实验室合作，研究了缺血引起的神经细胞凋亡和缺血引起的生殖细胞凋亡。共济失调毛细血管扩张突变 (Atm) 基因功能的丧失是由 IL-1β 介导的。(6) T 细胞依赖性抗体的产生受 IL-1β 调节，但不受 IL-1α 调节，通过诱导 CD40L 和 OX40 T 细胞。(7) 在接触性超敏反应的致敏阶段，接触过敏原特异性 T 细胞激活需要 IL-1α，而不是 IL-1β。(8)抑制 IL-1 KO 小鼠的自身免疫性关节炎，在这种小鼠中，由于 T 细胞上 CD40 配体和 OX40 表达水平低，T 细胞活化受到损害。在科学研究补助金的支持下，IL-1 的各种作用阐明了发热发展、应激反应、抗体产生、接触性超敏反应、类风湿性关节炎发展以及神经细胞和生殖细胞凋亡等方面的结果，这些结果和我们的 IL-1 基因 KO 小鼠可能非常有助于了解其机制。 IL-1 介导的人类疾病并开发针对这些疾病的医学治疗方法。