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

通过IL-1 α、IL-1 β、IL-Ira KO和IL-1 α/β双KO小鼠来阐明IL-1在动物体内的多效性功能，并阐明IL-1在免疫和应激反应中的作用。(1) IL-1 β，而非IL-1 α，在萜类激素诱导的发热和糖皮质激素分泌中起关键作用。(2)凋亡诱导剂Fas配体诱导的炎症是由IL-1 β介导的，IL-1 β的释放机制与caspase 1无关。(3) BALB/c背景下IL-Ira KO小鼠可自发发展为类似类风湿关节炎的慢性炎性关节病。(4) lps诱导的转基因小鼠HIV-1表达是由TNF α和IL-1介导的。(5)与其他实验室合作，IL-1β介导缺血引起的神经细胞凋亡和共济失调毛细血管扩张突变（Atm）基因功能丧失引起的生殖细胞凋亡。(6) T细胞依赖性抗体的产生受IL-1 β调控，而不受IL-1 α调控，通过诱导T细胞上的CD40L和OX40。(7)在接触过敏症的致敏期，接触过敏原特异性T细胞的活化需要IL-1α，而不需要IL-1β。(8) IL-1 KO小鼠自身免疫性关节炎的抑制，其中T细胞活化因CD40配体和OX40在T细胞上的低水平表达而受损。在科学研究资助项目的支持下，研究人员阐明了IL-1在发热、应激反应、抗体产生、接触性过敏、类风湿关节炎的发展以及神经细胞和生殖细胞凋亡中的各种作用。这些结果和我们的IL-1基因KO小鼠可能对了解IL-1介导的人类疾病的机制和开发药物治疗非常有用。

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.