2007 Fiscal Year Final Research Report Summary
Analysis of abnormal function of immunosuppressive intestinal macrophages in Crohn disease
| Project/Area Number |
18590700
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Keio University |
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Principal Investigator |
HISAMATSU Tadakazu Keio University, School of Medicine, Instructor (60255437)
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| Project Period (FY) |
2006 – 2007
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| Keywords | intestinal macrophage / Crohn disease / gut flora / M-CSF / pro-inflammatory cytokine / IL-23 / IFN-g |
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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
… More
, 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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[Journal Article] Unique CD14-positive intestinal macrophages contribute to the pathogen esis of Crohn's disease via IL-23/IFN-g axis2008
Author(s)
Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T, Sakuraba A, Kitazume M.T, Sugita A, Koganei K, Akagawa K.S, and Tosbifumi Hibi T.
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Journal Title
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Nonpathogenic Escherichia coli strain Nissle 1917 inhibits signal transd uction in intestinal epithelial cells2008
Author(s)
Kamada N, Maeda K, Inoue N, Hisamatsu T, Okamoto S, Hong KS, Yamada T, Watanabe N, Tsuchimoto K, Ogata H, Hibi T
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Journal Title
Infect Immun Jan;76(1)
Pages: 214-220
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Unique CD14-positive intestinal macrophages contribute to the pathogenesis of Crohn's disease via IL-23/IFN-g axis2008
Author(s)
Kamada, N., Hisamatsu, T., Okamoto, S., Chinen, H., Kobayashi, T., Sato, T., Sakuraba, A., Kitazume, M. T, Sugita, A., Koganei, K., Akagawa, KS., Toshifumi, Hibi, T
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Journal Title
J. Clin Invest 118(in press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Nonpathogenic Escherichia coli strain Nissie 1917 inhibits signal transduction in intestinal epithelial cells.2008
Author(s)
Kamada, N., Maeda, K., Inoue, N., Hisamatsu, T., Okamoto, S., Hong, KS, Yamada, T, Watanabe, N., Tsuchimoto, K., Ogata, H., Hibi T
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Journal Title
Infect Immun 76(1)
Pages: 214-220
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells2007
Author(s)
Chinen H, Matsuoka K, Sato T, Kamada N, Okamoto S, Hisamatsu T, Kobayashi T, Hasegawa H, Sugita A, Kinjo F, Fujita J, Hibi T
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Journal Title
Gastroenterology Aug;133(2)
Pages: 559-573
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells.2007
Author(s)
Chinen, H., Matsuoka, K., Sato, T., Kamada, N., Okamoto, S., Hisamatsu, T., Kobayashi, T., Hasegawa, H., Sugita, A., Kinjo, F., Fujita, J., Hibi, T
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Journal Title
Gastroenterology 133(2)
Pages: 559-573
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Exclusive increase of CX3CR1+CD28-CD4+ T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes.2007
Author(s)
Kobayashi, T., Okamoto, S., Iwakami, Y., Nakazawa, A., Hisamatsu, T., Chinen, H., Kamada, N., Imai, T., Goto, H., Hibi, T
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Journal Title
Inflamm Bowel Dis 13(7)
Pages: 837-846
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Abnormally differentiated intestinal macrophages in human Crohn's disease produce excess IL-23 in response to the enteric bacteria2007
Author(s)
Kamada, N., Hisamatsu, T., Chinen, H., Kobayashi, T., Okamoto, S., Hibi, T
Organizer
the 108th Annual Meeting of the AGA Institute
Place of Presentation
Washington DC
Year and Date
2007-05-21
Description
「研究成果報告書概要(欧文)」より
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