Studies on molecular regulation of the immune system

我们的研究项目由这项特别拨款支持，旨在从分子上剖析免疫系统，特别是关注白细胞介素-6（IL-6）。其中最重要的成果之一是发现了IL-6信号转导分子gp 130。我们证明，gp 130是利用作为一个信号转导器，也为其他几个细胞因子在免疫，造血，神经元和发育系统中发挥作用。gp 130等信号转导子的存在清楚地解释了细胞因子的功能冗余性。从我们的临床工作中可以清楚地看出，IL-6的过度表达与多种疾病的发病机制有关，如多发性骨髓瘤、Castleman病和AIDS相关的Kaposi肉瘤。此外，我们在Balb/c系的IL-6转基因小鼠中产生了具有（12;15）染色体易位的单克隆浆细胞瘤。为了了解IL-6相关疾病中IL-6的过度表达是如何发生的，已经研究了IL-6基因表达的调节。我们克隆了 ...更多信息 e参与IL-6基因表达的核因子NF-IL 6及其相关因子NF-IL 6 β。我们发现这两种分子能够形成异二聚体，在功能上相互协同。NF-IL 6和NF-kappaB以及HTLV-1的Tax之间的相互作用显示出协同作用。有助于IL-6启动子的激活。我们还证明了NF-IL 6和糖皮质激素受体之间的相互作用。这些结果为IL-6相关疾病的干预提供了线索。由于NF-IL-6还负责调节IL-6诱导的急性期蛋白基因，因此我们研究了IL-6在肝细胞中的信号转导过程。我们已经发现，IL-6刺激诱导gp 130的同源二聚化和相关的酪氨酸激酶激活，随后启动Ras-MAP激酶信号级联反应。鉴于<235>自身免疫性疾病的分子解剖，我们通过将来自MS患者的脑脊液的单核细胞转移到SCID小鼠的脑中，在小鼠中产生多发性硬化（MS）样病理。这项成果将为MS的研究提供一个动物模型。从上述结果以及我们在所附详细报告中记录的其他成果，可以得出结论，我们的研究活动得到了这项特别拨款的支持，是富有成效的，并提供了一个基础，更深入地了解，也是未来的临床方法，免疫疾病。少

Our research project supported by this special grant has aimed to molecularly dissect the immune system, especially focusing on interleukin-6(IL-6). One of the major achievements was finding of IL-6- signal transducer,gp130. We demonstrated that gp130 is utilized as a signal transducer also for several other cytokines functioning in immune, hematopoietic, neuronal, and developmental systems. Presence of the shared signal transducer like gp130 clearly explains functional redundancy of the cytokines.From our paraclinical work, it becomes clear that dysregulated overexpression of IL-6 is involved in the pathogenesis of various diseases, e.g. multiple myeloma, Castleman's disease, and AIDS-related Kaposi's sarcoma. Furthermore, we generated monoclonal plasmacytoma with (12;15) chromosomal translocation in the IL-6 transgenic mice of Balb/c strain. To understand how overexpression of IL-6 in the IL-6-related diseases occurrs, regulation of IL-6 gene expression has been studied. We cloned th … More e nuclear factors NF-IL6 and its relative, NF-IL6beta,that are involved in the IL-6 gene expression. We found that these two molecules are able to form heterodimers, functionally synergizing one another. Interactions between NF-IL6 and NF-kappaB as well as Tax of HTLV-1 were shown to synergistically. contribute to the activation of the IL-6 promoter. We also demonstrated interaction between NF-IL6 and glucocorticoid receptor. These results have provided a clue for intervention of IL-6-related diseases.Since NF-IL6 is responsible also for the regulation of IL-6-inducible acute phase protein genes, we have studied signaling processes of IL-6 in hepatocytes. We have found that IL-6-stimulation induces homodimerization of gp130 and associated tyrosine kinase activation which is followed by initiation of Ras-MAP kinase signaling cascades. This eventually results in the MAP kinase-dependent phosphorylation of Thr^<235> in NF-IL6,the critical step for its transcriptional activation.In view of the molecular dissection of autoimmune diseases, we generated multiple sclerosis (MS)- like pathology in mice by transferring mononuclear cells from the MS patient's cerebrospinal fluid into brains of SCID mice. This achievement will provide an animal model for the study of MS.From the above results together with our other achievements documented in the attached detailed report,it can be concluded that our research activities supported by this special grant are fruitful and have provided a basis for closer understanding of, and also future clinical approach to, the immune disorders. Less