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

为了阐明白介素6(IL-6)基因异常表达在免疫紊乱中起一定作用的分子机制(S)，我们首先提出了类风湿关节炎(RA)等自身免疫性疾病(S)发病机制的工作假说。我们推测内源性逆转录病毒的参与，以及病毒衍生的反式激活因子，如HTLV-1 p40Tax，可诱导包括IL-6基因在内的多种基因的表达，而IL-6基因的表达对疾病的发生至关重要。在这一假设的基础上，我们建立了克隆系统，最终可以克隆出存在于类风湿关节炎患者滑膜组织中的编码p40Tax样分子的基因。我们进一步证明HTLV-1p40Tax可以通过核因子-kB结合位点诱导IL-60基因的表达。此外，为了开发有效的IL-6作用抑制剂，我们研究了IL-6的信号转导。我们发现了JunB基因的一个新的IL-6反应元件(JRE-IL6)，并证明激活JRE-IL6的信号不包含PKC、PKA、ras和RAF的激活，这表明存在一条新的信号转导途径。

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.