Investigation of the molecular mechanisms of immunological disorders with abnormal expression of the interleukin 6 gene.

研究白细胞介素6基因异常表达的免疫性疾病的分子机制。

• 批准号: 02404032
• 负责人: HIRANO Toshio
• 金额: $ 24万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02404032/
• 关键词: Interleukin 6; autoimmune diseases; rheumatoid arthritis; signal transduction; receptor; インタ-ロイキン6; B細胞初期分化; 遺伝子発現; 接着因子; インタ-ロイキン; ウイルス

To elucidate the molecular mechanism(s) of immunological disorders where abnormal expression of the interleukin 6(IL-6) gene is considered to play some roles, we first made a working hypothesis of the pathogenesis of autoimmune disease(s) such as rheumatoid arthritis (RA). We postulate the involvement of endogenous retrovirus and that virus-derived transactivator, such as HTLV-1 p40tax would induce the expression of a variety of genes including the IL-6 gene of which expression is essential for disease onset. On the basis of this hypothesis, we established the cloning system by which we can ultimately clone the cDNA encoding p40tax like molecule present in the synovial tissue of RA patient. We further demonstrated that HTLV-1 p40tax can induce IL-60 gene expression through NF-kB binding site. Furthermore, to develop efficient inhibitors of IL-6 actions, we investigated the IL-6 signal transduction. We identified a novel IL-6 responsive element of the junB gene (JRE-IL6) and demonstrated that the signalings activating the JRE-IL6 does not contain PKC,PKA,ras,and raf activation, demonstrating the presence of a novel signal transduction pathway.

为了阐明白细胞介素6（IL-6）基因异常表达可能起作用的免疫疾病的分子机制，我们首先对自身免疫性疾病如类风湿关节炎（RA）的发病机制提出了一个工作假设。我们假设内源性逆转录病毒的参与，以及病毒衍生的反激活因子，如HTLV-1 p40tax，会诱导多种基因的表达，包括IL-6基因的表达，而IL-6基因的表达对疾病的发生至关重要。基于这一假设，我们建立了克隆系统，最终可以克隆RA患者滑膜组织中存在的编码p40tax样分子的cDNA。我们进一步证明HTLV-1 p40tax可以通过NF-kB结合位点诱导IL-60基因表达。此外，为了开发有效的IL-6抑制剂，我们研究了IL-6的信号转导。我们鉴定了junB基因的一个新的IL-6响应元件（JRE-IL6），并证明了激活JRE-IL6的信号不包含PKC、PKA、ras和raf激活，证明了一个新的信号转导途径的存在。

项目成果

Matsuda,T.,T.Nakajima,T.Kaisho,K.Nakajima and T.Hirano: "Interleukin 6 receptor and signal transduction. press." Adv.Biochem.Biol.Membrane. (1993)

Matsuda,T.,T.Nakajima,T.Kaisho,K.Nakajima 和 T.Hirano：“白细胞介素 6 受体和信号转导。按。”

Fujihashi,K.et al.: "Human appendix B cells Naturally express receptors for and respond to interleukin 6 with selective IgA1 and IgA2 synthesis." J.Clin.Invest.88. 248-252 (1991)

Fujihashi,K. 等人：“人类阑尾 B 细胞天然表达白细胞介素 6 受体并对其作出反应，并选择性合成 IgA1 和 IgA2。”

Nakajima,K.,T.Kusafuka,T.Takeda,Y.Fujitani,K.Nakae and T.Hirano: "Identification of a novel interleukin 6 responsive element composed of an Ets-binding site and a CRE-like site in the junB promoter. Mol.Cell.Biol." manuscript under revision. (1993)

Nakajima,K.,T.Kusafuka,T.Takeda,Y.Fujitani,K.Nakae 和 T.Hirano：“鉴定了由 junB 中的 Ets 结合位点和 CRE 样位点组成的新型白介素 6 响应元件

Hirano,T.,and T.Kishimoto: "Handbook of Experimental Pharmacology vol.95/I “Peptide Growth Factors and Their Receptors"" SpringerーVerlag, 35 (1990)

Hirano, T. 和 T. Kishimoto：“实验药理学手册第 95 卷/I “肽生长因子及其受体””Springer-Verlag，35 (1990)

Nakajima,K.et al: "Identification of a novel interleukin 6 responsive element composed of an Ets-binding site and a CRE-like site in the jinB promoter." Mol.Cell.Biol. (1993)

Nakajima,K.等人：“鉴定了一种新型白细胞介素 6 响应元件，该元件由 jinB 启动子中的 Ets 结合位点和 CRE 样位点组成。”