Analysis of abnormal function of immunosuppressive intestinal macrophages in Crohn disease

• Project/Area Number: 18590700
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: HISAMATSU Tadakazu Keio University, School of Medicine, Instructor (60255437)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥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)
• Keywords: intestinal macrophage / Crohn disease / gut flora / M-CSF / pro-inflammatory cytokine / IL-23 / IFN-g

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 , 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)

Research Products

• [Journal Article] Innate Immunity in IBD-State of the Art (2008)
  • Author(s): Hisamatsu T, Ogata H and Toshifumi Hibi T.
  • Journal Title: Current Opinion in Gastroenterology (in press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Unique CD14-positive intestinal macrophages contribute to the pathogen esis of Crohn's disease via IL-23/IFN-g axis (2008)
  • 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.
  • Journal Title: J.Clip Invest Vol.118
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Nonpathogenic Escherichia coli strain Nissle 1917 inhibits signal transd uction 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
  • 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
• [Journal Article] Innate Immunity in IBD - State of the Art (2008)
  • Author(s): Hisamatsu, T, Ogata, H., Toshifumi Hibi T
  • Journal Title: Current Opinion in Gastroenterology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Unique CD14-positive intestinal macrophages contribute to the pathogenesis of Crohn's disease via IL-23/IFN-g axis (2008)
  • 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
  • Journal Title: J. Clin Invest 118(in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Journal Title: Infect Immun 76(1) Pages: 214-220
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Unique CD14-positive intestinal macrophages contribute to the pathogenesis of Crohn's disease via IL-23/IFN-g axis (2008)
  • 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, Toshifumi Hibi T.
  • Journal Title: J. Clin Invest 118(6) Pages: 2269-2280
  • Peer Reviewed
• [Journal Article] Nonpathogenic Escherichia coli strain Nissle 1917 inhbits 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, Tsucbimoto K, Ogata H, Hibi T
  • Journal Title: Infect Immun. Jan;76(1) Pages: 214-220
  • Peer Reviewed
• [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
  • 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
• [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
  • Journal Title: Inflamm Bowel Dis Jul;13(7) Pages: 837-846
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [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
  • Journal Title: Gastroenterology 133(2) Pages: 559-573
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Journal Title: Inflamm Bowel Dis 13(7) Pages: 837-846
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Journal Title: Inflamm Bowel Dis. July;13(7) Pages: 837-846
  • Peer Reviewed
• [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, Hisamatsu T, Hibi T, etal
  • Journal Title: Inflamm Bowel Dis Feb 6 Pages: 1-10
• [Journal Article] Psychological aspects of inflammatory bowel disease. (2007)
  • Author(s): Hisamatsu T, Inoue N, Yajima T, Izumiya M, Ichikawa H, Hibi T
  • Journal Title: J Gastroenterol Jan;42
  • NAID: 10018539843
• [Journal Article] Cytomegalovirus is frequently reactivated and disappears without a antiviral agents in ulcerative colitis patients. (2006)
  • Author(s): Matsuoka K, Hisamatsu T, Hibi T, etal
  • Journal Title: Am J Gastroenterol Feb;102(2) Pages: 331-7
• [Journal Article] Centaurin betal down-regulates nucleotide-binding oligomerization domains 1- and 2-dependent NF-kappaB activation. (2006)
  • Author(s): Yamamoto-Furusho JK, Barnich N, Xavier R, Hisamatsu T, Podolsky DK
  • Journal Title: J Biol Chem Nov24;281(47) Pages: 36060-70
• [Journal Article] Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis (2006)
  • Author(s): Morohoshi Y, Hisamatsu T, Hibi T, etal
  • Journal Title: J Gastroenterol Apr;41(4) Pages: 318-24
  • NAID: 10018141558
• [Presentation] Unique intestinal denctritic cell-like macrophages contribute to the path ogenesis of Crohn's disease via IL-23/IFNg axis (2008)
  • Author(s): Tadakazu Hisamatsu
  • Organizer: 8th Colloquium for the Study of Gastrointestinal Defense System
  • Place of Presentation: Osaka
  • Year and Date: 2008-01-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Unique intestinal dendritic cell-like macrophages contribute to the pathogenesis of Crohn's disease via IL-23/IFNg axis. (2008)
  • Author(s): Tadakazu, Hisamatsu
  • Organizer: 8th Colloquium for the Study of Gastrointestinal Defense System
  • Place of Presentation: Osaka
  • Year and Date: 2008-01-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Unique intestinal dendritic cell-like macrophages contribute to the path ogenesis of Crohn's disease via IL-23/IFNg axis (2008)
  • Author(s): Tadakazu Hisamatsu
  • Organizer: 8th Colloquium for the Study of Gastrointestinal Defense System
  • Place of Presentation: Osaka
  • Year and Date: 2008-01-12
• [Presentation] Intestinal macrophages in human Crohn's disease produce excess IL-23 in response to commensal bacteria (2007)
  • Author(s): Kamada N, Hisamatsu T, Okamoto S, Chinen H, and Hibi T
  • Organizer: 13th International Congress of Mucosal Immunology
  • Place of Presentation: Tokyo
  • Year and Date: 2007-07-10
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Intestinal macrophages in human crohn's disease produce excess IL-23 in response to commensal bacteria (2007)
  • Author(s): Kamada N, Hisamatsu T, Okamoto S, Chinen H, Hibi T
  • Organizer: 13th International Congress of Mucosal Immunology
  • Place of Presentation: Tokyo
  • Year and Date: 2007-07-10
• [Presentation] Abnormally differentiated intestinal macrophages in human Crohn's disease produce excess IL-23 in response to the enteric bacteria (2007)
  • 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
• [Presentation] Abnormally differentiated intestinal macrophages in human crohn'sdisease produce excess IL-23 in response to the enteric bacteria (2007)
  • Author(s): Kamada N, Hisamatsu T, Chinen H, Kobayashi T, Okamoto S, Hibi T
  • Organizer: Digestive Disease Week and the 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington DC
  • Year and Date: 2007-05-21
• [Presentation] Abnormally differentiated intestinal macrophages in human Crohn's disease produce excess IL-23 in response to the enteric bacteria (2007)
  • Author(s): Kamada N, Hisamatsu T, Chinen H, Kobayashi T, Okamoto S, and Hibi T
  • Organizer: Digestive Disease Week and the 108th Annual Meeting of the AGA Institute
  • Place of Presentation: Washington DC
  • Year and Date: 2007-05-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Intestinal macrophages suppress excess immune response to enteric flor a and breaking it up causes intestinal inflammation (2007)
  • Author(s): Tadakazu Hisamatsu, Nobuhiko Kamada, Susumu Okamoto, and Toshifumi Hibi
  • Organizer: AGA-JSME joint symposium 第93回日本消化器病学会総会
  • Place of Presentation: 青森
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] クローン病における腸管マクロファージによる腸内細菌認識異常とTh-1誘導-マクロファージを中心とした炎症サイクル (2007)
  • Author(s): 久松 理一, 鎌田 信彦, 岡本 晋, 日比 紀文
  • Organizer: 第93回 日本消化器病学会総会 シンポジウム
  • Place of Presentation: 青森
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Intestinal macrophages suppress excess immune response to enteric flora and breaking it up causes intestinal inflammation. (2007)
  • Author(s): Tadakazu, Hisamatsu, Nobuhiko, Kamada, Susumu, Okamoto, Toshifumi, Hibi
  • Organizer: AGA-JSME joint symposium
  • Place of Presentation: Aomori
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Intestinal macrophages suppress excess immune response to enteric flora and breaking it up causes intestinal inflammation (2007)
  • Author(s): Tadakazu Hisamatsu, Nobubiko Kamada, Susumu Okamoto, Toshifumi Hibi
  • Organizer: AGA-JSME joint symposium第93回日本消化器病学会総会
  • Place of Presentation: 青森
• [Presentation] クローン病における腸管マクロファージによる腸内細菌認識異常とTh-1誘導-マクロファージを中心とした炎症サイクル- (2007)
  • Author(s): 久松 理一, 鎌田 信彦, 岡本 晋, 日比 紀文
  • Organizer: 第93回日本消化器病学会総会シンポジウム
  • Place of Presentation: 青森
• [Book] 腸管免疫研究の最前線-腸管の恒常性維持と炎症性腸疾患におけるその破綻-Annual Review 消化器2008 (2008)
  • Author(s): 久松 理一, 鎌田 信彦, 日比 紀文
  • Publisher: 中外医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] クローン病の発症と樹状細胞からのIL-23 臨床免疫、アレルギー科 49巻1号 (2008)
  • Author(s): 鎌田 信彦, 久松 理一, 岡本 晋, 日比 紀文
  • Publisher: 科学評論社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 腸管免疫研究の最前線-腸管の恒常性維持と炎症性腸疾患におけるその破綻 (2008)
  • Author(s): 久松 理一, 鎌田 信彦, 日比 紀文
  • Publisher: 中外医学社
• [Book] 腸管粘膜マクロファージによる腸管ホメオスターシスとその破綻 分子消化器病 vol.4 No.2 (2007)
  • Author(s): 鎌田 信彦, 久松 理一, 日比 紀文
  • Publisher: 先端医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] IL-10産生性抑制性腸管マクロファージの特殊性とIBD治療へのアプローチ IBD Research vol.1 no.3 (2007)
  • Author(s): 久松 理一, 鎌田 信彦, 日比 紀文
  • Publisher: 先端医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 慢性大腸炎とIL-12, IL-23産生マクロファージ 臨床免疫、アレルギー科 46巻4号 (2006)
  • Author(s): 久松 理一, 鎌田 信彦, 日比 紀文
  • Publisher: 科学評論社
  • Description: 「研究成果報告書概要(和文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://web.sc.itc.keio.ac.jp/medicine/ibd/index.html