Studies on molecular regulation of the immune system

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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