SEKI Noriyasu Mitubishi Welform, Researcher, 創薬第3研究所, 研究員
SAKAI Kaoru Mitubishi Welform, Researcher, 創薬第3研究所, 主任研究員
HASEGAWA Akihiro Pennsylvania University, Researcher
After the advanced economic growth, allergic disease, such as pollinosis, asthma and Atopic dermatitis, seriously become social problem in urban area of Japan.Although a steroid and immunosuppressant agent are so far commonly used for the therapeutic treatment of allergic patients, these treatment carried on the harmful side effect in some case, thus the development of novel therapeutic strategy to function more than the side effect would be necessary in the future.The serum of allergic patient contains large quantities of an immunoglobulin E antibody(IgB)reacting with allergen.IgE is secreted from plasma B cells after the class switch of the immunoglobulin gene, and Th2 derived cytokine, IL-4 regulates this class switch process.IL-4 controls the differentiation of Th2 and the IgB class switching in B cells by the signal pathway through its receptor.Therefore, JL-4 receptor mediated signaling pathway would be useful therapeutic target for allergic disease.
We established the two hybrid
system that monitor the interaction either between tyrosine-phosphorylated STAT6 and IL-4 receptor or homodimer of tyrosine-Phosphorylated STAT6, and using this system, we screen the compound to interfere these interaction.We confirmed the inhibitory effect of these compounds as an effect on the class switch of IgB and the activation of STAT6 mediated CD23 promoter activity.As a result of these extensive screening of 10000 compound, 2 compounds are found as candidates.The suppressors of the cytokine signaling(SOCS)protein are due to their action as a negative regulator of the cytokine signal, implicated in the determination of direction for Th1 and Th2 differentiation.We recently found that SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes.Since SOCS3 inhibits IL-12 mediated signaling through the binding with IL-12 receptor beta 2, we generate the screening system to monitor the interaction between SOCS3 and cytoplasmic region of IL-12 receptor beta 2.However, accuracy and sensitivity remain to be unresolved problem. Less