Formation of blood-brain barrier and activation of Interleukin-6 amplifier

• Project/Area Number: 24390098
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hokkaido University (2013-2014); Osaka University (2012)
• Principal Investigator: MURAKAMI Masaaki 北海道大学, 遺伝子病制御研究所, 教授 (00250514)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2014: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2012: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: 神経活性化 / 炎症回路 / 慢性炎症 / 神経反射シグナル / 血管内皮細胞 / 血管内皮 / 神経免疫 / 血液脳関門 / 炎症アンプ / 多発性硬化症

Outline of Final Research Achievements

Activation of NFkB and STAT induces massive production of chemokines in non-immune cells, which leads to local inflammation. We have been studying this inflammation amplifying mechanism, termed inflammation amplifier. In this study, we aimed to characterize mechanisms by which immune cells infiltrate into the central nervous system (CNS), and regulation of blood-brain barrier. In a murine model of multiple sclerosis, EAE, we found that high-performance MRI revealed that inflammation with edema occurred at fifth lumbar region where immune cells firstly enter the CNS. In addition, this edema was associated with ischemia/reperfusion injury that deteriorated the CNS inflammation. We also discovered that various stresses modulated the entry sites of immune cells into the CNS and altered the development of EAE in mice.

Research Products

• [Journal Article] Temporal expression of growth factors triggered by epiregulin regulates inflammation development. (2015)
  • Author(s): Harada, M., Kamimura, D., Arima, Y., Kohsaka, H., Nakatsuji, Y., Nishida, M., Atsumi, T., Meng, J., Bando, H., Singh, R., Sabharwal, L., Jiang, J. J., Kumai, N., Miyasaka, N., Sakoda, S., Yamauchi-Takihara, K., Ogura, H., Hirano, T. & Murakami, M.
  • Journal Title: J Immunol Volume: 194 Issue: 3 Pages: 1039-1046
  • DOI: 10.4049/jimmunol.1400562
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD147/Basigin limits lupus nephritis and TH17 cell differentiation by inhibiting the IL-6/STAT3 pathway. (2015)
  • Author(s): Maeda, K., T. Kosugi, W. Sato, H. Kojima, Y. Sato, D. Kamimura, N. Kato, N. Tsuboi, Y. Yuzawa, S. Matsuo, M. Murakami, S. Maruyama, K. Kadomatsu.
  • Journal Title: Arthritis Rheumatol. Volume: 印刷中 Issue: 8 Pages: 2185-2195
  • DOI: 10.1002/art.39155
  • Peer Reviewed / Open Access
• [Journal Article] Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. (2014)
  • Author(s): Hojyo S., T. Miyai, H. Fujishiro, M. Kawamura, T. Yasuda, A. Hijikata, B-H Bin, T. Irie, J. Tanaka, T. Atsumi, M. Murakami, M. Nakayama, O. Ohara, S. Himeno, H. Yoshida, H. Koseki, T. Ikawa, K. Mishima, and T. Fukada.
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 32 Pages: 11786-11791
  • DOI: 10.1073/pnas.1323557111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Gateway Reflex, which is mediated by the inflammation amplifier, directs pathogenic immune cells into the CNS. (2014)
  • Author(s): Sabharwal, L., Kamimura, D., Meng, J., Bando, H., Ogura, H., Nakayama, C., Jiang, J. J., Kumai, N., Suzuki, H., Atsumi, T., Arima, Y. & Murakami, M.
  • Journal Title: Journal of biochemistry Volume: 156 Issue: 6 Pages: 299-304
  • DOI: 10.1093/jb/mvu057
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inflammation Amplifier, a New Paradigm in Cancer Biology (2014)
  • Author(s): Atsumi T, Singh R, et al.
  • Journal Title: Cancer Research Volume: 74 Issue: 1 Pages: 8-14
  • DOI: 10.1158/0008-5472.can-13-2322
  • Peer Reviewed
• [Journal Article] The reverse-direction method links mass experimental data to human diseases. (2014)
  • Author(s): Ogura, H., Atsumi, T., Bando, H., Sabharwal, L., Yamada, M., Jiang, J. J., Nakamura, A., Arima, Y., Kamimura, D. & Murakami, M
  • Journal Title: Archivum immunologiae et therapiae experimentalis Volume: 62 Issue: 1 Pages: 41-45
  • DOI: 10.1007/s00005-013-0255-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Early pathological alterations of lower lumber cords detected by ultra-high field MRI in a mouse multiple sclerosis model. (2014)
  • Author(s): Mori, Y, M. Murakami, Y. Arima, D. Zhu, Y. Terayama, Y. Komai, Y. Nakatsuji, D. Kamimura, and Y. Yoshioka
  • Journal Title: Int Immunol. Volume: 26 Issue: 2 Pages: 93-101
  • DOI: 10.1093/intimm/dxt044
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of Immune Cell Infiltration into the CNS by Regional Neural Inputs Explained by the Gate Theory. (2013)
  • Author(s): Arima Y, D. Kamimura, L. Sabharwal, M. Yamada, H. Bando, H. Ogura, T. Atsumi and M Murakami.
  • Journal Title: Mediators of Inflammation Volume: 898165 Pages: 8-16
  • DOI: 10.1155/2013/898165
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The gateway theory : bridging neural and immune interactions in the CNS (2013)
  • Author(s): Kamimura D, Yamada M, Harada M, et al.
  • Journal Title: Frontiers in Neuroscience Volume: 7 Pages: 204-204
  • DOI: 10.3389/fnins.2013.00204
  • Peer Reviewed
• [Journal Article] Reverse direction method: A possible tool to link animal models with corresponding human diseases and disorders. (2013)
  • Author(s): Singh, R., T Atsumi, H Bando, M Harada, A Nakamura, M Yamada, J-J Jiang, H Suzuki, K Katsunuma, T Nodomi, D Kamimura, H Ogura, M Murakami.
  • Journal Title: Int. J. Genomic Med. Volume: 1 Pages: 1-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Gate Theory Explains Regional Neural Regulation of Activated T cells Entering the Central Nervous System. (2013)
  • Author(s): Kamimura, D., M Yamada, L Sabharwal, H Ogura, Y Okuyama, A Nakamura, T Atsumi, Y Arima, M Murakami.
  • Journal Title: Journal of Clinical & Cellular Immunology Volume: 4 Issue: 04 Pages: 156-156
  • DOI: 10.4172/2155-9899.1000156
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Disease-Association Analysis of an Inflammation-Related Feedback Loop. (2013)
  • Author(s): Murakami M, Harada M, Kamimura D
  • Journal Title: Cell Reports Volume: 3 Issue: 3 Pages: 946-59
  • DOI: 10.1016/j.celrep.2013.01.028
  • Peer Reviewed
• [Journal Article] Autoimmune disorder phenotypes in HVCN1 gene deficient mice. (2013)
  • Author(s): Sasaki M, Tojo A, Okochi Y, Miyawaki N, Kamimura D, Yamaguchi A, Murakami M, Okamura Y.
  • Journal Title: Biochem J Volume: 450 Issue: 2 Pages: 295-301
  • DOI: 10.1042/bj20121188
  • Peer Reviewed
• [Journal Article] IL-6 amplifier activation in epithelial regions of bronchi after allogeneic lung transplantation. (2013)
  • Author(s): Lee, J.*, T. Nakagiri*, D. Kamimura*, (*equal contribution), M. Harada, T. Inoue, S. Miyoshi, E. Morii, T. Hirano, M. Murakami, and M. Okumura
  • Journal Title: Int lmmunol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] ENTPDase7 controls Th17 cell responses through regulation of luminal ATP in the small intestine. (2013)
  • Author(s): Kusu, T., et al.
  • Journal Title: J. Immunol. Volume: 190 Issue: 2 Pages: 774-783
  • DOI: 10.4049/jimmunol.1103067
  • Peer Reviewed
• [Journal Article] IL-6アンプルートと関連分子 (2013)
  • Author(s): 小椋英樹、村上正晃
  • Journal Title: 臨床免疫・アレルギー科 Volume: 59 Pages: 265-273
  • Peer Reviewed
• [Journal Article] EAEと血液脳関門 (2013)
  • Author(s): 村上正晃
  • Journal Title: 医学のあゆみ Volume: (in press)
• [Journal Article] IL-6アンプと血液脳関門への病原Th17の侵入口形成 (2013)
  • Author(s): 上村大輪、小椋英樹、村上正晃
  • Journal Title: 炎症と免疫 Volume: 21 Pages: 108-116
• [Journal Article] 特異的T細胞が関与しない関節炎の発症機序 (2013)
  • Author(s): 奥山祐子、村上正晃
  • Journal Title: 臨床免疫・アレルギー科 Volume: 59 Pages: 232-239
  • NAID: 40019594166
• [Journal Article] IL-6 ampliferと免疫・神経クロストーク (2013)
  • Author(s): 有馬康伸、村上正晃
  • Journal Title: 医薬ジャーナル Volume: 49 Pages: 109-116
• [Journal Article] IL-6 amplifier, NF-κB-triggered positive feedback for IL-6 signaling, in grafts is involved in allogeneic rejection responses. (2012)
  • Author(s): Lee J
  • Journal Title: Journal of Immunology Volume: 189 Issue: 4 Pages: 1928-1936
  • DOI: 10.4049/jimmunol.1103613
  • Peer Reviewed
• [Journal Article] Intestinal CX3C chemokine receptor 1high (CX3CR1high) myeloid cells prevent T-cell-dependent colitis (2012)
  • Author(s): Kayama, H, et al
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: (In press) Issue: 13 Pages: 5010-5015
  • DOI: 10.1073/pnas.1114931109
  • Peer Reviewed
• [Journal Article] The Molecular Mechanisms of Chronic Inflammation Development. (2012)
  • Author(s): Murakami, M.
  • Journal Title: Front. Immunol. Volume: 3 Pages: 323-323
  • DOI: 10.3389/fimmu.2012.00323
  • Peer Reviewed
• [Journal Article] The pathological and physiological roles of IL-6 amplifier activation. (2012)
  • Author(s): Murakami, M.
  • Journal Title: Int. J. Biol. Sci. Volume: 8 Issue: 9 Pages: 267-1280
  • DOI: 10.7150/ijbs.4828
  • Peer Reviewed
• [Journal Article] IL-6アンプと中枢神経系のゲート (2012)
  • Author(s): 村上正晃
  • Journal Title: 感染・炎症・免疫
• [Journal Article] 細胞性免疫(T細胞免疫) (2012)
  • Author(s): 村上正晃
  • Journal Title: 免疫学コア講義 Volume: 11 Pages: 113-120
• [Journal Article] IL-6と受容体系経路 (2012)
  • Author(s): 村上正晃、有馬康伸、平野俊夫
  • Journal Title: 日本臨床増刊号 分指標的薬 Volume: 11 Pages: 192-206
• [Journal Article] IL-6アンプの活性化と中枢神経系臓器への免疫細胞の侵入口形成 (2012)
  • Author(s): 村上正晃、有馬康伸、上村大輔
  • Journal Title: 感染・炎症・免疫 Volume: 42 Pages: 210-220
• [Journal Article] インターロイキン6による神経系と免疫系の融合 (2012)
  • Author(s): 有馬康伸、村上正晃
  • Journal Title: 領域融合レビュー Volume: 10
• [Presentation] 炎症回路の神経制御とリンパ球に与える影響 (2015)
  • Author(s): 村上正晃
  • Organizer: 第39回日本リンパ学会総会
  • Place of Presentation: お茶の水ソラシティーカンファレンスセンター（東京都千代田区）
  • Year and Date: 2015-03-27 – 2015-03-29
  • Invited
• [Presentation] 炎症回路と慢性炎症 (2015)
  • Author(s): 村上正晃
  • Organizer: 第120回日本解剖学会・第92回日本生理学会合同大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-03-21 – 2015-03-23
  • Invited
• [Presentation] Regional neural regulation of inflammation amplifier (2014)
  • Author(s): 村上正晃
  • Organizer: Cytokines Down Under 2014: From Bench to Beyond
  • Place of Presentation: Melbourne Convention & Exhibition Center (オーストラリア、メルボルン)
  • Year and Date: 2014-10-26 – 2014-10-29
  • Invited
• [Presentation] Local neural activation enhances inflammation responses (2014)
  • Author(s): 村上正晃
  • Organizer: 理研IMS-日本免疫学会合同国際シンポジウム2014
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-06-26 – 2014-06-27
  • Invited
• [Presentation] 血液脳関門に存在する免疫細胞の侵入口の発見とその形成機構 (2014)
  • Author(s): 村上正晃
  • Organizer: 第79回日本インターフェロン・サイトカイン学会シンポジウム
  • Place of Presentation: 北海道大学医学部フラテホール（北海道札幌市）
  • Year and Date: 2014-06-19 – 2014-06-20
  • Invited
• [Presentation] 血液脳関門への免疫細胞の侵入口の形成-局所神経刺激と炎症アンプの役割- (2013)
  • Author(s): 村上正晃
  • Organizer: 第13回神経・筋の免疫疾患を考える会、教育セミナー
  • Place of Presentation: ホテル阪急インターナショナル(大阪)(招待講演)
  • Year and Date: 2013-02-23
• [Presentation] 教育レビュートーク「活性化T細胞と中枢神経系の病気、病態」 (2012)
  • Author(s): 村上正晃
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他(招待講演)
  • Year and Date: 2012-12-05
• [Presentation] Local neural pathway and a gateway for pathogenic T cells in the CNS (2012)
  • Author(s): 村上正晃
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他(招待講演)
  • Year and Date: 2012-12-05
• [Presentation] 病原T細胞の中枢神経系への侵入口の形成メカニズム-非免疫細胞の炎症誘導機構"IL-6アンプ"の役割- (2012)
  • Author(s): 村上正晃
  • Organizer: 平成24年度北海道大学獣医学研究科学術交流基金群講演会
  • Place of Presentation: 北海道大学獣医学研究科(招待講演)
  • Year and Date: 2012-11-01
• [Presentation] 局所の神経活性化による自己免疫病の制御 (2012)
  • Author(s): 村上正晃
  • Organizer: 名古屋大学グローバルCOEプログラム-系統講義ニューロサイエンスコース 第5回セミナー
  • Place of Presentation: 名古屋大学医学系研究科(招待講演)
  • Year and Date: 2012-10-18
• [Presentation] 局所の神経活性化による病原性T細胞の中枢移行メカニズム (2012)
  • Author(s): 村上正晃
  • Organizer: 厚生労働省科学研究費補助金(難治性疾思克服研究事業)神経変性疾患に関する調査研究班平成24年度「病態に根ざしたALSの新規治療法開発」分科班ワークショップ
  • Place of Presentation: シェーンバッハ・サボー(砂防会館別館、東京)(招待講演)
  • Year and Date: 2012-10-05
• [Presentation] 中枢神経系への免疫細胞の侵入メカニズム (2012)
  • Author(s): 村上正晃
  • Organizer: 第40回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル(招待講演)
  • Year and Date: 2012-09-27
• [Presentation] 血液脳関門への免疫細胞の侵入口の形成と自己免疫疾患 (2012)
  • Author(s): 村上正晃
  • Organizer: 第12回がん・エピゲノム研究会特別講演
  • Place of Presentation: 東北大学(招待講演)
  • Year and Date: 2012-07-11
• [Presentation] 神経刺激による血液脳関門への免疫細胞の侵入口の形成 (2012)
  • Author(s): 村上正晃
  • Organizer: 第22回サイトメトリー学会学術集会-ランチョンセミナー
  • Place of Presentation: ライフサイエンスセンター(大阪)(招待講演)
  • Year and Date: 2012-06-30
• [Presentation] 非免疫細胞に存在する炎症誘導機構、IL-6アンプ (2012)
  • Author(s): 村上正晃
  • Organizer: 北海道大学遺伝子病制御研究所セミナー
  • Place of Presentation: 北海道大学遺伝子病制御研究所(招待講演)
  • Year and Date: 2012-06-22
• [Presentation] 神経刺激による血液脳関門の血管の制御:自己反応性T細胞の侵入口の形成 (2012)
  • Author(s): 村上正晃
  • Organizer: 第46回北摂循環器研究会
  • Place of Presentation: 大阪大学銀杏会館(招待講演)
  • Year and Date: 2012-06-06
• [Presentation] 炎症の誘導機構『IL-6アンプ』と関節炎 (2012)
  • Author(s): 村上正晃
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪 国際館パミール(招待講演)
  • Year and Date: 2012-04-28
• [Presentation] IL-6 amplifier activation in donors plays a role in allogenic rejection responses (2012)
  • Author(s): 李 智慧
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Epiregulin is involved in inflammation development via IL-6 amplifier activation (2012)
  • Author(s): 原田誠也
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Regional neural activation directly influences immune signals in the central nervous system via the IL-6 amplifier activation. (2012)
  • Author(s): 有馬康伸
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Characterization of an ENU-mutant mouse with impaired T-cell homeostasis. (2012)
  • Author(s): 上村大輔
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] L6 amplifier, NF-kB-triggered positive-feedback for IL-6 signahg, is a key player in inflammation associated with various human diseases. (2012)
  • Author(s): 小椋英樹
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] PTKN is critical for IL-6 amplifier activation via NTF-kB activation. (2012)
  • Author(s): 孟 潔
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] SAG1 positively regulates NFkB signaling pathway via enhancing IkBa ubiquitination and promotes inflammatory disease development (2012)
  • Author(s): 奥山祐子
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Molecular-x, which is a novel MTF-1 target gene regulates the IL-6 amplifier activation via NFKB activation. (2012)
  • Author(s): 大坪亮太
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] A protein kinase, PKN IS involved in the IL-6 amplifier activation by regulating chromatin activation of NF-κB target genes. (2012)
  • Author(s): 諸井亜理紗
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Effector T cell functions and neuro-immune interactions. (2012)
  • Author(s): 村上正晃
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場他(招待講演)
• [Book] Cytokine Frontiers: Regulation of Immune Responses in Heal th and Disease (2013)
  • Author(s): Kamimura, D., H. Ogura, Y. Arima, T. Hirano, and M. Murakam
  • Publisher: (IL-6 and inflammatory diseases. (in press)
• [Remarks] 北海道大学遺伝子病制御研究所分子神経免疫学分野
  • URL: http://www.igm.hokudai.ac.jp/neuroimmune/Eindex.html