Analysis of innate IL-5 producing cells in immune responses and chronic inflammation

• Project/Area Number: 24390119
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: University of Toyama
• Principal Investigator: TAKATSU Kiyoshi 富山大学, 大学院医学薬学研究部(医学), 客員教授 (10107055)
• Co-Investigator(Kenkyū-buntansha): NAGAI Yoshinori 富山大学, 大学院医学薬学研究部(医学), 客員准教授 (30431761) ; IKUTANI Masashi 富山大学, 大学院医学薬学研究部(医学), 客員講師 (40513718) ; 刈米 アイ 富山大学, 大学院・医学薬学研究部, 客員助教 (50114450) ; 小笠原 勝 富山県薬事研究所, 主任研究員 (30443427)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2012: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: サイトカイン / 自然免疫 / 粘膜免疫 / 免疫監視・腫瘍免疫 / 好酸球

Outline of Final Research Achievements

In this study, we investigated the roles of innate IL-5-producing cells in the lung and the intestine by taking advantage of IL-5/Venus knock-in mice. In response to IL-25 or IL-33, innate IL-5-producing cells rapidly produced IL-5 and IL-13. These cells were localized around bronchus and bronchioles and recruited eosinophil into the lung, suggesting that innate IL-5-producing cells play a critical role in the pathogenesis of allergic conditions. Innate IL-5-producing cells in the lung also contributed to anti-tumor immunity via eosinophil regulation. On the other hand, in the large intestine, innate IL-5-producing cells contributed to T cell-independent IgA production.

Research Products

• [Journal Article] Differential requirements of MyD88 And TRIF pathways in TLR4-mediated immune responses in murine B cells. (2015)
  • Author(s): Yanagibashi T., Nagai Y., Watanabe Y., Ikutani M., Hirai Y., Takatsu K.
  • Journal Title: Immunology Letters Volume: 163 Issue: 1 Pages: 22-31
  • DOI: 10.1016/j.imlet.2014.11.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Increased production of intestinal immunoglobulins in Syntenin-1-deficient mice. (2015)
  • Author(s): Tamura K., Ikutani M., Yoshida T., Tanaka-Hayashi A., Yanagibashi T., Inoue R., Nagai Y., Adachi Y., Miyawaki T., Takatsu K., Mori H.
  • Journal Title: Immunobiology Volume: 220 Issue: 5 Pages: 597-604
  • DOI: 10.1016/j.imbio.2014.12.003
  • Peer Reviewed
• [Journal Article] Inflammation-induced endothelial cell-derived extracellukar vesicles modulate the cellular status of pericytes. (2015)
  • Author(s): Yamamoto S., Niida S., Azuma E., Yanagibashi T., Muramatsu M., Huang TT., Sagara H., Higaki S., Ikutani M., Nagai Y., Takatsu K., Miyazaki K., Hamashima T., Mori H., Matsuda N., Ishii Y., Sasahara M.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 8505-8505
  • DOI: 10.1038/srep08505
  • Peer Reviewed / Open Access
• [Journal Article] Revisiting the identification and cDNA cloning of T cell-replacing factor/interleukin-5. (2015)
  • Author(s): Takatsu K.
  • Journal Title: Frontiers in Immunology Volume: 5 Pages: 639-639
  • DOI: 10.3389/fimmu.2014.00639
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Deficiency of nicotinamide mononucleotide adenylyltransferase 3 (nmnat3) causes Hemolytic anemia by altering the glycolytic flow in mature erythrocytes. (2014)
  • Author(s): Hikosaka K., Ikutani M., Shito M., Kazuma K., Gulshan M., Nagai Y., Takatsu K., Konno K., Tobe K., Kanno H., Nakagawa T.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 21 Pages: 14796-14811
  • DOI: 10.1074/jbc.m114.554378
  • Peer Reviewed
• [Journal Article] Lnk prevents inflammatory CD8+ T-cell proliferation and contributes to intestinal homeostasis. (2014)
  • Author(s): Katayama H., Mori T., Seki Y., Anraku M., Iseki M., Ikutani M., Iwasaki Y., Yoshida N., Takatsu K., Takaki S.
  • Journal Title: European Journal of Immunology Volume: 44 Issue: 6 Pages: 1622-1632
  • DOI: 10.1002/eji.201343883
  • Peer Reviewed / Open Access
• [Journal Article] Lnk/Sh2b3 controls the production and function of dendritic cells, regulates the induction of IFN-gamma-producing T cells. (2014)
  • Author(s): Mori T., Iwasaki Y., Seki Y., Iseki M., Katayama H., Yamamoto K., Takatsu K., Takaki S.
  • Journal Title: The Journal of Immunology Volume: 193 Issue: 4 Pages: 1728-36
  • DOI: 10.4049/jimmunol.1303243
  • Peer Reviewed / Open Access
• [Journal Article] Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. (2014)
  • Author(s): Honda H., Nagai Y., Matsunaga T., Okamoto N., Watanabe Y., Tsuneyama K., Hayashi H., Fujii I., Ikutani M., Hirai Y., Muraguchi A., Takatsu K.
  • Journal Title: Journal of Leukocyte Biology Volume: 96 Issue: 6 Pages: 1087-1100
  • DOI: 10.1189/jlb.3a0114-005rr
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Roles of IL-5-producing group 2 innate lymphoid cells in eosinophil regulation. (2014)
  • Author(s): Ikutani M., Takatsu K.
  • Journal Title: Inflammation and Regeneration Volume: 34 Pages: 140-142
  • NAID: 130004943859
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Adipose Tissue Hypoxia Induces Inflammatory M1 Polarity of Macrophages in HIF-1a-Dependent and HIF-1a-Independent Manners in Obese Mice. (2013)
  • Author(s): Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, Mahmood A, Goda N, Nagai Y, Takatsu K, Tobe K..
  • Journal Title: Diabetologia Volume: 56(6) Issue: 6 Pages: 1403-1412
  • DOI: 10.1007/s00125-013-2885-1
  • Peer Reviewed
• [Journal Article] Interleukin 5 plays a key Role in mouse strain-dependent susceptibility to contact hypersensitivity through its effects on initiator B cells. (2013)
  • Author(s): Atsuko Itakura, Masashi Ikutani, Kiyoshi Takatsu, Yuji Kikuchi
  • Journal Title: International Archives of Allergy and Immunology Volume: 161 Issue: Suppl. 2 Pages: 98-106
  • DOI: 10.1159/000350367
  • Peer Reviewed
• [Journal Article] The TLR family protein RP105/MD-1 complex: a new player in obesity and adipose tissue inflammation (2013)
  • Author(s): Yoshinori Nagai, Yasuharu Watanabe, Kiyoshi Takatsu
  • Journal Title: Adipocyte Volume: 2 Issue: 2 Pages: 61-66
  • DOI: 10.4161/adip.22929
  • Peer Reviewed
• [Journal Article] Activation and regulation of the pattern recognition receptors in obesity-induced adipose tissue inflammation and insulin resistance (2013)
  • Author(s): Yasuharu Watanabe, Yoshinori Nagai, Kiyoshi Takatsu
  • Journal Title: Nutrients Volume: 5 Issue: 9 Pages: 3757-3778
  • DOI: 10.3390/nu5093757
  • Peer Reviewed
• [Journal Article] 自然免疫系受容体RP105/MD-1によるメタボリック症候群の制御 (2013)
  • Author(s): 長井良憲, 渡邉康春, 高津聖志
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 37 Pages: 611-616
• [Journal Article] Analysis of Trichophyton antigen-induced contact hypersensitivity in mouse (2012)
  • Author(s): Nakamura, T., et al.
  • Journal Title: Journal of Dermatological Science Volume: (in press) Issue: 2 Pages: 144-153
  • DOI: 10.1016/j.jdermsci.2012.02.008
  • Peer Reviewed
• [Journal Article] Glycyrrhizin and isoliquiritigenin suppress the LPS sensor Toll-like receptor 4/MD-2 complex signaling in a different manner. (2012)
  • Author(s): Hiroe Honda
  • Journal Title: Journal of Leukocyte Biology Volume: 91 Pages: 967-976
  • Peer Reviewed
• [Journal Article] Structural basis of interleukin-5 dimer recognition by its alpha receptor (2012)
  • Author(s): Kusano S., Kukimoto-Niino M., Hino N., Ohsawa N., Ikutani M., Takaki S., Sakamoto K., Hara-Yokoyama M., Shirouzu M., Takatsu K., Yokoyama S
  • Journal Title: Protein Sci Volume: 21 Issue: 6 Pages: 850-864
  • DOI: 10.1002/pro.2072
  • Peer Reviewed
• [Journal Article] Tetrameric interaction of the ectoenzyme CD38 on the cell surface enables its catalytic and raft-association activities. (2012)
  • Author(s): Miki Hara - Yokoyama
  • Journal Title: Structure Volume: 20 Pages: 1585-1595
  • Peer Reviewed
• [Presentation] Roles of IL-5-producing ILC2 in vascular pathogenesis (2014)
  • Author(s): Ikutani Masashi, Tsuneyama Koichi, Nagai Yoshinori, Takatsu Kiyoshi
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Adipocyte-derived free fatty acids trigger IL-1β production by neutrophils in mouse adipose tissue (2014)
  • Author(s): Yasuharu Watanabe, Yoshinori Nagai, Koichi Tsuneyama, Kiyoshi Takatsu
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation (2014)
  • Author(s): Hiroe Honda, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] An antibiotics funiculosin derivative is a novel agonist of Toll-like receptor 4 (2014)
  • Author(s): Naoki Okamoto, Hiroe Honda, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 副腎白質ジストロフィーモデルマウスへの骨髄移植とその効果 (2014)
  • Author(s): 松本隼, 守田雅志, 渡邉康春, 長井良憲, 小林博司, 山本誠士, 石井陽子, 笹原正清, 高津聖志, 今中常雄
  • Organizer: 日本薬学会北陸支部第126回例会
  • Place of Presentation: 金沢大学角間キャンパス（金沢）
  • Year and Date: 2014-11-16
• [Presentation] 副腎白質ジストロフィー：レンチウイルスベクターによるABCD1タンパク質の発現と骨髄移植 (2014)
  • Author(s): 松本隼, 守田雅志, 渡邉康春, 長井良憲, 小林博司, 高津聖志, 今中常雄
  • Organizer: 第56回日本先天代謝異常学会総会
  • Place of Presentation: 江陽グランドホテル（仙台）
  • Year and Date: 2014-11-13 – 2014-11-15
• [Presentation] 遊離脂肪酸誘発性の内臓脂肪組織炎症における好中球とIL-1シグナルの機能解析脂肪酸誘発性の内臓脂肪組織炎症における好中球とIL-1シグナルの機能解析 (2014)
  • Author(s): 長井良憲, 渡邉康春, 高津聖志
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: フェニックスシーガイアリゾート コンベンションセンター（宮崎）
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] Structural determination and synthesis of isoprenoids as immune activators via TLR4/MD-2 (2014)
  • Author(s): Mizote Keisuke, Saeki Akinori, Honda Hiroe, Okamoto Naoki, Kimura Takahito, Nagai Yoshinori, Takatsu Kiyoshi, Fujimoto Yukari, Fukase Koichi
  • Organizer: 2014 SLB IEIIS Meeting
  • Place of Presentation: Salt Lake City Sheraton（アメリカ合衆国）
  • Year and Date: 2014-10-23 – 2014-10-25
• [Presentation] モデルマウスを用いた副腎白質ジストロフィーに対する骨髄移植の検討マウスを用いた副腎白質ジストロフィーに対する骨髄移植の検討 (2014)
  • Author(s): 松本隼, 守田雅志, 渡邉康春, 長井良憲, 小林博司, 高津聖志, 今中常雄
  • Organizer: 日本薬学会第13回次世代を担う若手ファーマ・バイオフォーラム2014
  • Place of Presentation: 富山国際会議場（富山）
  • Year and Date: 2014-09-20 – 2014-09-21
• [Presentation] IL-33に誘導される血管壁肥厚とIL-5産生ILC2 (2014)
  • Author(s): 生谷尚士, 常山幸一, 長井良憲, 高津聖志
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館（沖縄）
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] Isoliquiritigenin and glycyrrhizin inhibit the inflammasome activation in a different manner (2013)
  • Author(s): Hiroe Honda, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: The 100th Annual Meeting of The American Association of Immunologists(第100回アメリカ免疫学会)
  • Place of Presentation: Hawaii Convention Center(アメリカ合衆国）
• [Presentation] Regulatory mechanisms of Radioprotective 105/MD-1 expression in inflammatory macrophages in the adipose tissue (2013)
  • Author(s): Yasuharu Watanabe, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第78回日本インターフェロン・サイトカイン学会, 第21回マクロファージ分子細胞生物学国際シンポジウム 合同学術集会
  • Place of Presentation: 都市センターホテル（東京）
• [Presentation] 腸管免疫におけるIL-5産生ILC2の役割の解明 (2013)
  • Author(s): 生谷尚士, 柳橋努, 長井良憲, 高津聖志
  • Organizer: 第34回日本炎症・再生医学会
  • Place of Presentation: 国立京都国際会館（京都）
• [Presentation] メタボリック症候群における慢性炎症を制御する自然免疫シグナルの解析 (2013)
  • Author(s): 長井良憲, 渡邉康春, 本田裕恵, 戸邉一之, 高津聖志
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京国際フォーラム（東京）
• [Presentation] 自然免疫受容体TLR4/MD-2複合体の新規リガンド創製を目指したイソプレノイド脂質の構造解析と合成研究 (2013)
  • Author(s): 溝手啓介, 佐伯昭典, 本田裕恵, 岡本直樹, 木村隆仁, 長井良憲, 高津聖志, 藤本ゆかり, 深瀬浩一
  • Organizer: 日本化学会秋季事業 第3回CSJ化学フェスタ2013
  • Place of Presentation: タワーホール船堀（東京）
• [Presentation] 副腎白質ジストロフィー: レンチウイルスベクターを用いたABCD1遺伝子発現と骨髄移植 (2013)
  • Author(s): 松本隼, 守田雅志, 渡邉康春, 長井良憲, 小林博司, 高津聖志, 今中常雄
  • Organizer: 平成25年度日本薬学会北陸支部第125回例会
  • Place of Presentation: 北陸大学薬学部アネックスファーム（石川）
• [Presentation] 甘草成分はTLR4及びNLRP3インフラマソーム活性化を阻害する (2013)
  • Author(s): 本田裕恵, 長井良憲, 高村（赤司）祥子, 齋藤伸一郎, 三宅健介, 高津聖志
  • Organizer: 第19回日本エンドトキシン・自然免疫研究会
  • Place of Presentation: ロイヤルオークホテル スパ＆ガーデンズ（滋賀）
• [Presentation] The roles of IL-5 producing ILC2 in the intestinal immunity (2013)
  • Author(s): Tsutomu Yanagibashi, Masashi Ikutani, Yoshinori Nagai, Kiyoshi Takatsu
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ（千葉）
• [Presentation] β3-adrenergic receptor-mediated lipolysis of adipocytes induces accumulation of large number of neutrophils and pro-inflammatory responses in mouse adipose tissue (2013)
  • Author(s): Yasuharu Watanabe, Yoshinori Nagai, Koichi Tsuneyama, Kiyoshi Takatsu
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ（千葉）
• [Presentation] Characterization of innate IL-5-producing non-T cells in the large intestine regarding responsiveness to IL-33 and IgA production. (2012)
  • Author(s): 柳橋努
  • Organizer: 第41回日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2012-12-07
• [Presentation] Isoliquiritigenin and glycyrrhizin, representative components of Glycyrrhiza uralensis, inhibit activation of NALP3 inflammasome. (2012)
  • Author(s): 本田裕恵
  • Organizer: 第41回日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2012-12-06
• [Presentation] Roles of lung innate IL-5-producing cells in antimetastatic activitythrough eosinophils. (2012)
  • Author(s): 生谷尚士
  • Organizer: 第12回国際エンドトキシン・自然免疫学会 (IEIIS2012)
  • Place of Presentation: 学術総合センター(東京都)
  • Year and Date: 2012-10-24
• [Presentation] Regulatory roles of innate IL-5-producing non-T cells in the immune surveillance in the lung and IgA production in the intestine. (2012)
  • Author(s): 高津聖志
  • Organizer: 第20回マクロファージ分子細胞生物学国際シンポジウム
  • Place of Presentation: 東京大学山上会館(東京都)(招待講演)
  • Year and Date: 2012-06-15
• [Book] 第4章 13節 RP105. 「seriesモデル動物利用マニュアル 疾患モデルの作製と利用ー脂質代謝異常と関連疾患<下巻>」. 尾池雄一, 佐々木雄彦, 村上誠, 矢作直也編集. (2015)
  • Author(s): 長井良憲, 渡邉康春, 高津聖志
  • Total Pages: 10
  • Publisher: 株式会社エル・アイ・シー
• [Book] 第6章 3 植物由来成分によるTLR4/MD-2シグナルの抑制. エンドトキシン・自然免疫研究17. 谷徹, 横地高志編集. (2014)
  • Author(s): 本田裕恵, 長井良憲, 高津聖志
  • Total Pages: 6
  • Publisher: 医学図書出版株式会社
• [Book] Chapter 5 Eosinophilopoiesis: Chapter 5.4 Interleukin-5 and its Receptor molecules, In “Eosinophil in Health and Disease” (Eds. J.J. Lee and H.F. Rosenberg) (2014)
  • Author(s): Kiyoshi Takatsu
  • Total Pages: 9
  • Publisher: ELSEVIER/Academic Press
• [Book] Section2. Part E. 26. Role of the immune system in obesity-associated inflammation and insulin resistance. In "Nutrition in the Prevention and Treatment of Abdominal Obesity" (Ronald R. Watson) (2014)
  • Author(s): Yoshinori Nagai, Kiyoshi Takatsu
  • Total Pages: 13
  • Publisher: ELSEVIER/Academic Press
• [Remarks] 富山大学大学院医学薬学研究部（医学）免疫バイオ・創薬探索研究講座 高津研究室
  • URL: http://www.med.u-toyama.ac.jp/immbio/index.html
• [Remarks] 富山大学大学院医学薬学研究部（医学）免疫バイオ・創薬探索研究講座 高津研究室
  • URL: http://www.med.u-toyama.ac.jp/immbio/index.html
• [Remarks] 研究室ホームページ
  • URL: http://www.med.u-toyama.ac.jp/immbio/
• [Patent(Industrial Property Rights)] トール様受容体4活性化作用を有するフニクロシン誘導体及びその用途 (2014)
  • Inventor(s): 藤本ゆかり，深瀬浩一，髙津聖志，長井良憲，岡本直樹
  • Industrial Property Rights Holder: 藤本ゆかり，深瀬浩一，髙津聖志，長井良憲，岡本直樹
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-201593
  • Filing Date: 2014-09-30
• [Patent(Industrial Property Rights)] IL-1及びTNF活性阻害剤 (2014)
  • Inventor(s): 髙津聖志，平井嘉勝，長井良憲，松永孝之
  • Industrial Property Rights Holder: 髙津聖志，平井嘉勝，長井良憲，松永孝之
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-12-24
  • Overseas
• [Patent(Industrial Property Rights)] ヒト肺高血圧症に類似した病態を示すモデル動物及びその作成方法 (2013)
  • Inventor(s): 生谷 尚士，髙津 聖志，常山 幸一，川口 誠，福岡 順也
  • Industrial Property Rights Holder: 生谷 尚士，髙津 聖志，常山 幸一，川口 誠，福岡 順也
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-183870
  • Filing Date: 2013-09-05
• [Patent(Industrial Property Rights)] トール様受容体4活性化作用を有するフニクロシン誘導体及びその用途 (2013)
  • Inventor(s): 藤本 ゆかり，深瀬 浩一，髙津 聖志，長井 良憲，岡本 直樹
  • Industrial Property Rights Holder: 藤本 ゆかり，深瀬 浩一，髙津 聖志，長井 良憲，岡本 直樹
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-203801
  • Filing Date: 2013-09-30
• [Patent(Industrial Property Rights)] IL-1及びTNF活性阻害剤 (2013)
  • Inventor(s): 髙津 聖志，平井 嘉勝，長井 良憲，松永 孝之
  • Industrial Property Rights Holder: 髙津 聖志，平井 嘉勝，長井 良憲，松永 孝之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-271897
  • Filing Date: 2013-12-27
• [Patent(Industrial Property Rights)] インフラマソーム活性制御剤 (2012)
  • Inventor(s): 高津 聖志, 平井 嘉勝, 長井 良憲, 松永 孝之, 本田 裕恵
  • Industrial Property Rights Holder: 富山大学 富山県薬事研究所
  • Industrial Property Number: 2012-247766
  • Filing Date: 2012-11-09