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

建立了IL-1α、IL-1β、IL-Ira KO和IL-1α/β双重KO小鼠，以阐明IL-1在动物体内的多效性，并阐明了IL-1在免疫和应激反应中的作用如下：(1)IL-1β，而不是IL-1α，在松节油诱导的发热和糖皮质激素分泌中起关键作用。(2)由凋亡诱导剂Fas配体诱导的炎症是由IL-1β介导的，该炎症是由caspase 1独立的机制释放的。(3)在BALB/c背景下，IL-ira KO小鼠自发地发生类似类风湿性关节炎的慢性炎性关节病。(4)在转基因小鼠中，脂多糖诱导的HIV-1的表达是由肿瘤坏死因子α和IL-1介导的。(5)与其他实验室合作，IL-1β可通过诱导T细胞表面CD40L和OX40调节T细胞依赖性抗体的产生，但不受IL-1β的调节。(7)IL-1α可调节T细胞依赖性抗体的产生，但不受IL-1α的调节。(8)抑制IL-1 KO小鼠的自身免疫性关节炎，其中T细胞由于CD40配体和T细胞上OX40的低水平表达而受损。在对科学研究补助金的支持下，阐明了IL-1在发热发生、应激反应、抗体产生、接触性超敏反应、类风湿性关节炎发生以及神经细胞和生殖细胞的凋亡中的各种作用。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治疗这些疾病的药物非常有用。

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.