Development of the epigenetic treatment against inflammatory bowel disease with targeting chromatin remodeling

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1.Examination of therapeutic effect in the mouse experimental colitisA single or combination administration of DNA methylation inhibitor (Aza-dC) and histone deacetylase (HDAC) inhibitor (FK228) was evaluated on therapeutic efficacy for the mouse DSS colitis.Colitis was induced by 3% DSS for four days ad libitum in Balb/c mouse.We divided it into our groups : DNA methylation inhibitor (Aza-dC) single administration group, HDAC inhibitor (FK228) single administration group, combined administration group, and control group and we explored the preventive and therapeutic effect of treatment.As a result, colitis rather accepted a tendency to worsen in an Aza-dC single administration group, while colitis was ameliorated in the combination group, which did not reach a statistically significant difference comparing with the control group, but preventive and therapeutic effect of treatment in FK228 group was proven.We next examined mouse TNBS colitis, where significant preventive and therapeutic effect of treatment in FK228 group was only demonstrated in DSS colitis.2.The in vivo analysis of the anti-inflammatory action mechanism of HDAC inhibitorWe reviewed various cytokine profiles using colonic tissue in the mouse TNBS colitis by ELISA.As a result, TNFα, IFN-γ, and IL-6 expression was decreased in a dose-dependent manner, but a significant difference was not found in IL-10 expression level.Furthermore, we isolated lamina propria lymphocytes (LPMC) from DSS colitis, and acetylation of H3 was detected in a FK228 dose-dependent manner revealed by Western blotting using an anti acetyl-histone (H3) antibody.3.Examination of the epigenetic abnormality in the experimental colitisWe genome-widely analyze gene expression changes with the chemical administration by cDNA array, and candidate genes whose silencing is canceled and expressing are going to be checked the chromatin remodeling state of the promoter region of those in future.