| Budget Amount *help |
¥3,860,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
Backgland/Aims; Omega-3 polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are enriched in fish oils, are held to be beneficial in a wide range of human inflammatory disorders, including inflammatory bowel disease (IBD), but the molecular mechanism was unknown. Recently, Resolvin E1 (RvE1), an endogenous lipid mediator induced from EPA was identified when generated in local inflammation at the healing stage by the enzymes such as cycloocygenase-2 and 5-lipoxygenase. It was reported that RvE1 inhibited the migration of dendritic cells in the spleen in vivo and the production of 1L-12 in vitro after the stimulation with the pathogen extracts derived from Toxoplasma gondii soluble tachyzoite antigen. In addition, we have reported that RvE1 protected against TNBS-induced colitis in mice which was known to Th1-dominant acute colitis model. However it remains to be seen which immune cells expressed RvE1 receptor (ChemR23) which was re
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cently identified in detail and the mechanism to regulate the colonic inflammation. Methods/Results; The cells expressing ChemR23 in mice was investigated using the monoclonal antibody. ChemR23 expressed mostly in mouse intraperitoneal macrophage. Therefore, intraperitoneal macrophages were pretreated with RvE1, followed by stimulation with LPS and then, mRNA of the proinflammatory cytokines were analyzed by real time RT-PCR. The treatment with RvE1 led to the inhibition of IL-12p40, TNF-a, additionally IL-10, TGF-β. Next, since it is known that NFKb plays a role in cytokine regulation, we assessed whether nuclear translocation of NFKb could be inhibited by the pretreatment with RvE1 after the stimulation. To do so, HEK 293 transfectant cells with ChemR23 or mock cells which were pretreated with RvEl or control were stimulated with TNF-α and then, stained with anti-NF-kBp65 antibody. RvE1 pretreatment inhibits TNF-α-induced nuclear translocation of NF-kB by the dependent manner of ChemR23. These results suggested that RvE1 could regulate immune response on macrophage expressing ChemR23. Therefore, we investigated the beneficial effect of RvE1 in dextran sulfate sodium (DSS) induced colitis which was independent with T cells and B cells. The administration of 3.5%DSS in 8weeks-old C57BL16 or Ragl-deficient female mice was induced severe colitis. RvE1 treatment, however, led to protect DSS colitis about clinical findings and histological score. Conclusion: These data suggest that RvE1 was effective for Th1-dominant disease, but also the suppression of macrophage induced inflammation. Therefore these data suggested that RvE1 may be one of new treatment of many kinds of chronic inflammatory disease including human inflammatory bowel disease. Less
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