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

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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.