The roles of cytokines on the development of rheumatoid arthritis

细胞因子在类风湿关节炎发生发展中的作用

• 批准号: 12470076
• 负责人: IWAKURA Yoichiro
• 金额: $ 9.02万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470076/
• 关键词: Rheumatoid Arthritis; Animal Models1; IL-1; HTLV-I; IL-6; TNF-α; IL-17; IL-1R antagonist; 自己免疫疾患; トランスジェニックマウス; ノックアウトマウス; HTLV-1

We have produced transgenic mice carrying tax gene of HTLV-I (HTLV-I Tg) and IL-1 receptor antagonist knockout (IL-1Ra KO) mice, and found these mice spontaneously develop autoimmune arthritis. Also, we have reported that T cell dependent cellular immunity is crucial for the development of the disease. In this project, we evaluated that the roles of cytokine on the development of the autoimmune arthritis using those 2 mouse models. We showed that IL-1 and IL-6 is crucial for the development of the disease of HTLV-I Tg and TNF-a is required in the disease of IL-1Ra KO mice. Unlike other cytokines, IL-17 is known to be produced by the activated CD4 T cells, and induces other cytokines and chemokines. Also, it is suggested to be involved in rheumatoid arthritis in humans, because this cytokine is detected in the joints of the patients. Then, we produced IL-17 knockout (IL-17 KO) mice, and found that IL-17 deficiency completely suppresses the disease in the IL-1Ra KO mice.

我们制备了携带HTLV-Ⅰ tax基因的转基因小鼠（HTLV-Ⅰ Tg）和IL-1受体拮抗剂敲除小鼠（IL-1 Ra KO），发现这些小鼠自发发生自身免疫性关节炎。此外，我们已经报道了T细胞依赖性细胞免疫对于疾病的发展至关重要。本课题利用这两种小鼠模型，评价细胞因子在自身免疫性关节炎发生发展中的作用。我们发现IL-1和IL-6对HTLV-I Tg疾病的发展至关重要，而TNF-α是IL-1 Ra KO小鼠疾病所需的。与其他细胞因子不同，已知IL-17由活化的CD 4 T细胞产生，并诱导其他细胞因子和趋化因子。此外，它被认为是参与类风湿性关节炎在人类中，因为这种细胞因子是在患者的关节中检测到的。然后，我们产生了IL-17敲除（IL-17 KO）小鼠，并且发现IL-17缺陷完全抑制了IL-1 Ra KO小鼠中的疾病。

项目成果

Miura,T.: "Roles of endogenous cytokines in liver apoptosis of mice in lethal Listeria monocytogenes infection."FEMS Immunol.Med.Microbiol.. 28. 335-341 (2000)

Miura,T.：“内源性细胞因子在致死性单核细胞增多性李斯特菌感染小鼠肝细胞凋亡中的作用。”FEMS 免疫学医学微生物学 28. 335-341 (2000)

Nakae, S.: "IL-1-induced TNE elicits inflammatory cell infiltration in the skin by inducing interferon-g-inducible protein-10 in the elicitation phase of CHS"Int. Immunol.. 15. 251-260 (2003)

Nakae, S.：“IL-1 诱导的 TNE 通过在 CHS 诱发阶段诱导干扰素 G 诱导蛋白 10 来诱发皮肤中的炎症细胞浸润”Int。

Nagai, Y.: "Requirement for MD-1 in Cell Surface Expression of RP105/CD180 and B Cell Responsiveness to Lipopolysaccharide"Blood. 99. 1699-1705 (2002)

Nagai, Y.：“RP105/CD180 细胞表面表达中 MD-1 的要求和 B 细胞对脂多糖的反应”血液。

Saijo, S.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD40L and OX40 expression on T cell"Arth. Rheum.. 13. 533-544 (2002)

Saijo, S.：“在 IL-1 缺陷小鼠中抑制自身免疫性关节炎，其中 T 细胞活化因 T 细胞上低水平的 CD40L 和 OX40 表达而受损”Arth。

Iwakura, Y.: "Autoimmune chronic inflammatory arthropathy in mice transgenic for the HTLV-I tax gene"Gann Monograph. (in press). (2003)

Iwakura, Y.：“HTLV-I Tax 基因转基因小鼠的自身免疫性慢性炎症性关节病”江恩专着。