| Budget Amount *help |
¥3,820,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
We have been studying the role of intestinal macrophage for gut immune homeostasis and inflammation. We have reported that wild type murine intestinal macropahges are similar phenotype to M-CSF dependent macrophages in vitro. They have pahagocytotic function and produce rapid response cytokines, TNFa and IL-6, while they never produce IL-l2 and IL-23 known as Th-1/Th-17 induced cytokine in response to bacteria. They also produce high amount of IL-10. Thus, intestinal macrophages play a important role to suppress excess immune response to commensal and inhibit Th-1/Th-17 chronic inflammation. We also found that endogenous IL-10 is necessary for differentiation to immunosuppressive intestinal macrophages. In IL-10 KO mice, which is well-known as a model of Th-1 dominant colitis, bone marrow derived M-CSF dependent macrophages and intestinal macrophages produced abnormally high amount of IL-l2 and IL-23 in response to bacteria and. Lead to Th-I dominant inflammation (Kamada N, Hisamatsu T
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, et al. J. Immunol 2005). Furthermore, we have been studying functional roles of intestinal macrophages in human Crohn's disease (CD). We found that the differentiation of peripheral blood monocyte to macrophages by M-CSF was disturbed in some CD patients, but not all. Decrease of endogenous IL-10 production could cause to this result. Next, we investigated intestinal macrophages in human CD patients. In intestinal mucosa of CD, number of CD14+CD33+ unique intestinal macrophage subset was increased. They also expressed typical macrophage marker CD68 and exhibit spindle shaped adherent cells. This CD14+CD33+ intestinal macrophages isolated from CD patients produced higher amount of IL-23 compared to ulcerative colitis patients (UC) and normal control (NL) inresponse to E. coli and E. feacalis. IL-23 produced by those unique macrophages stimulated IFN production by T cells and NK cells in lamina propria and lead to Th-1 dominant inflammation. IFN-also affected to the intestinal macrophage differentiation process by M-CSF. IFN-altered macrophage phenotype to more IL-23 hyper productive one. Thus, we demonstrated that abnormal function of intestinal macrophages, especially IL-23/IFN- axis, plays important roles in the pathogenesis of human CD (Kamada N, Hisamatsu T, Hibi T, et al. J. Clin Invest in press) Less
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