Characterization of intracellular Zn signaling and its relationship to diseases

• Project/Area Number: 24249028
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: HIRANO Toshio 大阪大学, その他部局等, 学長 (40136718)
• Co-Investigator(Kenkyū-buntansha): MURAKAMI Masaaki 北海道大学, 遺伝子病制御研究所, 教授 (00250514) ; 深田 俊幸 独立行政法人理化学研究所, アレルギー科学総合研究センター, 研究員 (70373363) ; 西田 圭吾 独立行政法人理化学研究所, アレルギー科学総合研究センター, 研究員 (80360618) ; 山崎 哲 独立行政法人理化学研究所, アレルギー科学総合研究センター, 研究員 (30392161)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥46,020,000 (Direct Cost: ¥35,400,000、Indirect Cost: ¥10,620,000); Fiscal Year 2014: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2013: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2012: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
• Keywords: 亜鉛シグナル / 自己免疫疾患 / 炎症回路 / MTF1 / カスペース / 細胞内亜鉛信号 / 免疫反応 / 亜鉛恒常性

Outline of Final Research Achievements

Zinc is one of the essential metal elements, which is indispensable for the functions of various molecules in the body. However, it is not well understood how zinc levels inside and/or outside cells are regulated. In the course of research about interleukin-6 and its signal transduction, we found that zinc acts as a second messenger in a cell, and established a scientific field of “zinc signaling”. In this study, we revealed molecular mechanisms and physiological functions of zinc signaling using various knock-out mice related to zinc signaling such as zinc-binding molecules and zinc transporters.

Research Products

• [Journal Article] Zinc-binding metallothioneins are key modulators of IL-4 production by basophils (2015)
  • Author(s): Ugajin T, Nishida K, Yamasaki S, Suzuki J, Mita M, Kubo M, Yokozeki H, Hirano T
  • Journal Title: Mol Immunol Volume: 66 Issue: 2 Pages: 180-188
  • DOI: 10.1016/j.molimm.2015.03.002
  • Peer Reviewed / Acknowledgement Compliant
• [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] Revisiting the 1986 molecular cloning of interleukin 6. (2014)
  • Author(s): Hirano T
  • Journal Title: Front Immunol. Volume: 5 Pages: 456-456
  • DOI: 10.3389/fimmu.2014.00456
  • 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] 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: 106-106
  • 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] The Gate Theory: How Regional Neural Activation Creates a Gateway for Immune Cells via an Inflammation Amplifier. (2013)
  • Author(s): Ogura H, Y. Arima, D. Kamimura, M Murakami
  • Journal Title: Biomedical J Volume: 36 Issue: 6 Pages: 269-273
  • DOI: 10.4103/2319-4170.113187
  • 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] 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.
  • Journal Title: Int Immunol. Volume: in press
  • Peer Reviewed
• [Journal Article] ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders (2013)
  • Author(s): Nam, H, C-Y. Wang, L. Zhang, W. Zhang, S. Hojyo, T. Fukada, and M. Knutson
  • Journal Title: Haematologica Volume: 未定 Issue: 7 Pages: 1049-1057
  • DOI: 10.3324/haematol.2012.072314
  • Peer Reviewed
• [Journal Article] Zinc signal: a new player in osteobiology (2013)
  • Author(s): Fukada T, Hojyo S, Furuichi T.
  • Journal Title: Journal of Bone and Mineral Metabolism Volume: 31 Issue: 2 Pages: 129-135
  • DOI: 10.1007/s00774-012-0409-6
  • NAID: 10031168847
  • 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] Vaccination with antigen-transfected, NKT cell ligand-loaded, human cells elicits robust in situ immune responses by dendritic cells. (2013)
  • Author(s): Shimizu K, Mizuno T, Shinga J, Asakura M, Kakimi K, Ishii Y, Masuda K, Maeda T, Sugahara H, Sato Y, Matsushita H, Nishida K, Hanada K, Dorrie J, Schaft N, Bickham K, Koike H, Ando T, Nagai R, Fujii S.
  • Journal Title: Cancer Res. Volume: 73(1) Issue: 1 Pages: 62-73
  • DOI: 10.1158/0008-5472.can-12-0759
  • 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] A novel role of the L-type calcium channelα1D subunit as a gatekeeper for intracellular zinc signaling : Zinc wave. (2012)
  • Author(s): Yamasaki S, et al.
  • Journal Title: PLoS ONE Volume: (in Press) Issue: 6 Pages: 3488-3495
  • DOI: 10.1371/journal.pone.0039654
  • Peer Reviewed
• [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] 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] Critical role of P1-Runx1 in mouse basophil development. (2012)
  • Author(s): Mukai K.
  • Journal Title: Circulation Journal. Volume: 76 Pages: 2031-2040
  • Peer Reviewed
• [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: - 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 Volume: - Pages: 192-206
• [Journal Article] IL-6と受容体経路 (2012)
  • Author(s): 村上正晃
  • Journal Title: 日本臨床 Volume: -
• [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] Local neural pathway and a gateway for pathogenic T cells in the CNS (2012)
  • Author(s): 村上正晃
  • Organizer: Symposium 2012 Annual meeting of Japanese society for immunology
  • Place of Presentation: 神戸国際会議場他
  • Invited
• [Presentation] 免疫アレルギーとZn(亜鉛)
  • Author(s): 平野俊夫
  • Organizer: 皮膚アレルギー・接触皮膚炎学会
  • Place of Presentation: 軽井沢プリンスホテル
  • Invited
• [Presentation] The roles of IL-6 amplifier in autoimmune diseases
  • Author(s): 平野俊夫
  • Organizer: CREST「免疫機構」領域－CREST/さきがけ「慢性炎症」領域合同国際シンポジウム
  • Place of Presentation: 一橋記念講堂(東京)
  • Invited
• [Presentation] 亜鉛シグナルと成長・骨代謝
  • Author(s): 深田俊幸
  • Organizer: 第66回日本栄養・食糧学会大会 シンポジウム
  • Place of Presentation: 東北大学他
  • Invited
• [Presentation] 『亜鉛シグナル』：全身成長と骨代謝に関わる新しいシグナル伝達機構
  • Author(s): 深田俊幸
  • Organizer: 第12回日本抗加齢医学会・総会 シンポジウム
  • Place of Presentation: パシフィコ横浜
  • Invited
• [Presentation] 亜鉛シグナル研究とメタロミクス：その可能性・期待・課題について
  • Author(s): 深田俊幸
  • Organizer: 第23回日本微量元素学会学術大会 ワークショップ
  • Place of Presentation: シェーンバッハ・サボー
  • Invited
• [Presentation] 新規エーラス・ダンロス症候群に関わる亜鉛トランスポーターZIP13の生化学的解析 -ヒトZIP13蛋白質はホモ２量体を形成する
  • Author(s): 深田俊幸
  • Organizer: 第23回日本微量元素学会学術大会 リサーチシンポジウム１
  • Place of Presentation: シェーンバッハ・サボー
  • Invited
• [Presentation] 亜鉛トランスポーター、ZnT5/Slc39a5は遅延型アレルギー、接触性皮膚炎反応に重要である
  • Author(s): 西田圭吾
  • Organizer: 第23回日本微量元素学術集会 リサーチシンポジウム
  • Place of Presentation: シェーンバッハ・サボー
  • Invited
• [Presentation] L型カルシウムチャネルによる細胞内亜鉛シグナル伝達と免疫反応
  • Author(s): 山崎哲
  • Organizer: 第７回トランスポーター研究会年会
  • Place of Presentation: 京都大学農学部
• [Presentation] メタロチオネイン（MT）による好塩基球のIL-4産生制御
  • Author(s): 宇賀神つかさ
  • Organizer: 第62回日本アレルギー学術秋季学術大会
  • Place of Presentation: 大阪国際会議場
• [Presentation] Metallothionein (MT) regulates IL-4 production from basophil
  • Author(s): 賀神つかさ
  • Organizer: 第41回日本免疫学会総会 ワークショップ
  • Place of Presentation: 神戸国際会議場他
• [Presentation] LTCC-mediated intracellular Zn signaling positively regulates cytokine production in mast cells
  • Author(s): Yamasaki S.
  • Organizer: 第41回日本免疫学会総会 ワークショップ
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Zinc signal: A new regulatory system in bone and immunity
  • Author(s): 深田俊幸
  • Organizer: 第85回日本生化学会大会 シンポジウム
  • Place of Presentation: 福岡国際会議場他
• [Presentation] 細胞内亜鉛シグナルによるマスト細胞活性化と炎症反応
  • Author(s): 山崎哲
  • Organizer: 第85回日本生化学会大会 シンポジウム
  • Place of Presentation: 福岡国際会議場他
  • Invited
• [Presentation] Zinc signal: the action of Zn ion controlling cellular and physiological events
  • Author(s): 深田俊幸
  • Organizer: 第86回日本薬理学会年会 シンポジウム
  • Place of Presentation: 福岡国際会議場
• [Book] Cytokine Frontiers: Regulation of Immune Responses in Health and Disease (2013)
  • Author(s): Kamimura D.
  • Publisher: IL-6 and inflammatory diseases.