• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

The role of unfolded protein responses in cholera toxin-induced immune adjuvant effect

Research Project

Project/Area Number 19K07628
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49070:Immunology-related
Research InstitutionWakayama Medical University

Principal Investigator

Sasaki Izumi  和歌山県立医科大学, 先端医学研究所, 講師 (80611037)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsコレラ毒素 / NLRP3インフラマソーム / Pyrinインフラマソーム / IL-1beta / 腹腔マクロファージ / IL-1β / IRE1α / インフラマソーム / 小胞体ストレス応答 / 小胞体ストレス
Outline of Research at the Start

コレラ毒素は、免疫アジュバント(免疫増強剤)として機能し、炎症性サイトカインの産生や、感染症やがんに対する防御免疫を増強する。しかし、その作用機序は不明である。我々は、コレラ毒素が小胞体ストレス応答を誘導し、この誘導が炎症性サイトカインの産生に必要であることを見出した。本研究ではこの結果を検証し、コレラ毒素による免疫アジュバント活性における小胞体ストレス応答の機能的意義を解明する。小胞体ストレスは、糖尿病などの病態形成に関与するが、その分子機序は不明である。本研究は免疫アジュバント活性の新しい分子機序の解明だけでなく、種々の疾患の新規治療薬開発にも貢献することが期待される。

Outline of Final Research Achievements

Cholera toxin (CT) is a strong immune adjuvant that can induce production of pro-inflammatory cytokines. Previously, we found that CTB, a subunit of CT, produces large amounts of pro-inflammatory cytokine, interleukin-1 beta (IL-1β) from lipopolysaccharide-stimulated murine resident peritoneal macrophages (RPMs). However, it remains unclear how CTB induces IL-1β production. In this research, we try to clarify this point. We found that CTB induces ER-stress related genes and activate ER stress sensor IRE1α. Furthermore, we clarified that IRE1α is involved in CTB-induced IL-1β production from RPMs by using IRE1α selective inhibitor.
In conclusion, our findings indicate that CTB is a novel ER stress inducer and IRE1α is involved in CTB-induced IL-1β production from RPMs.

Academic Significance and Societal Importance of the Research Achievements

小胞体ストレスは、糖尿病などの病態形成に関与するが、その分子機序の解析は基本的に培養細胞を用いて検討されており、生体内の細胞における分子機構は不明な部分が多い。また、免疫アジュバント活性における小胞体ストレス応答の意義もよくわかっていない。本研究により、生体内のマクロファージにおける小胞体ストレス応答機構が明らかとなり、この機構がCTBによる炎症性サイトカインIL-1βの産生誘導に関与するというユニークな知見を得た。本研究は免疫アジュバント活性の新しい分子機序の解明だけでなく、小胞体ストレスが関与する種々の疾患の新規治療薬開発にも貢献することが期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (26 results)

All 2021 2020 2019

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (19 results) (of which Int'l Joint Research: 5 results)

  • [Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency2021

    • Author(s)
      Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 0-0

    • DOI

      10.1038/s41467-021-27085-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Augmentation of STING‐induced type I interferon production in COPA syndrome2021

    • Author(s)
      Kato Takashi、Yamamoto Masaki、Honda Yoshitaka、Orimo Takashi、Sasaki Izumi、Murakami Kohei、Hemmi Hiroaki、Fukuda‐Ohta Yuri、Isono Kyoichi、Takayama Saki、Nakamura Hidenori、Otsuki Yoshiro、Miyamoto Toshiaki、Takita Junko、Yasumi Takahiro、Nishikomori Ryuta、Matsubayashi Tadashi、Izawa Kazushi、Kaisho Tsuneyasu
    • Journal Title

      Arthritis & Rheumatology

      Volume: in press Issue: 11 Pages: 2105-2115

    • DOI

      10.1002/art.41790

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade2020

    • Author(s)
      Mizumoto Y, Hemmi H, Katsuda M, Miyazawa M, Kitahata Y, Miyamoto A, Nakamori M, Ojima T, Matsuda K, Nakamura M, Hayata K, Fukuda-Ohta Y, Sugiyama M, Ohta T, Orimo T, Okura S, Sasaki I, Tamada K, Yamaue H, Kaisho T.
    • Journal Title

      British Journal of Cancer

      Volume: 122 Issue: 8 Pages: 1185-1193

    • DOI

      10.1038/s41416-020-0757-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The mechanism of action of Spi-B in the transcriptional activation of the interferon-α4 gene.2020

    • Author(s)
      R. Miyazaki, H. Saiga, T. Kato, T. Bakoshi, R. Senba, A. Shintani, M. Suzuki, K. Takao, I. Sasaki, A. Iizuka, M. Sugiyama, N. Iwami, Y. Fukuda-Ohta, H. Hemmi, T. Tanaka, M. Miyake, T. Kaisho, K. Hoshino.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 30;525 Issue: 2 Pages: 477-482

    • DOI

      10.1016/j.bbrc.2020.02.101

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a novel CCDC22 mutation in a patient with severe Epstein?Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia2019

    • Author(s)
      Yamashita Y, Nishikawa A, Iwahashi Y, Fujimoto M, Sasaki I, Mishima H, Kinoshita A, Hemmi H, Kanazawa N, Ohshima K, Imadome KI, Murata SI、Yoshiura KI, Kaisho T, Sonoki T, Tamura S
    • Journal Title

      International Journal of Hematology

      Volume: 印刷中 Issue: 6 Pages: 744-750

    • DOI

      10.1007/s12185-019-02595-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cholera toxin B induces interleukin-1β production from resident peritoneal macrophages through the pyrin inflammasome as well as the NLRP3 inflammasome2019

    • Author(s)
      Orimo T, Sasaki I, Hemmi H, Ozasa T, Fukuda-Ohta Y, Ohta T, Morinaka M, Kitauchi M, Yamaguchi T, Sato Y, Tanaka T, Hoshino K, Katayama KI, Fukuda S, Miyake K, Yamamoto M, Satoh T, Furukawa K, Kuroda E, Ishii KJ, Takeda K, Kaisho T
    • Journal Title

      International Immunology

      Volume: 印刷中 Issue: 10 Pages: 657-668

    • DOI

      10.1093/intimm/dxz004

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9‐genome editing promotes antitumor immunity and suppresses ovarian cancer progression2019

    • Author(s)
      Yahata T, Mizoguchi M, Kimura A, Orimo T, Toujima S, Kuninaka Y, Nosaka M, Ishida Y, Sasaki I, Fukuda‐Ohta Y, Hemmi H, Iwahashi N, Noguchi T, Kaisho T, Kondo T, Ino K
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 4 Pages: 1279-1292

    • DOI

      10.1111/cas.13958

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] コレラ毒素Bサブユニットによる免疫アジュバント活性における小胞体ストレスセンサーIRE1aの機能的意義2021

    • Author(s)
      佐々木 泉, 改正 恒康
    • Organizer
      第34回日本バイオセラピィ学会学術集会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Critical roles of IRE1a in cholera toxin-induced interleukin-1b production from resident peritoneal macrophages2021

    • Author(s)
      Izumi Sasaki, Yuri Fukuda-Ohta, Naoko Wakaki-Nishiyama, Chihiro Nakai, Shuhei Morita, Daisuke Okuzaki, Mika Kaku, Kanta Sawase, Asumi Yamamoto, Takashi Kato, Takashi Orimo, Ko-ichi Furukawa, Tsuneyasu Kaisho
    • Organizer
      16th Meeting of the International Endotoxin and Innate Immunity Society (IEIIS 2021)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] An endoplasmic reticulum stress sensor IRE1a is involved in cholera toxin-induced interleukin-1b production from tissue resident macrophages2021

    • Author(s)
      Izumi Sasaki, Yuri Fukuda-Ohta, Naoko Wakaki-Nishiyama, Chihiro Nakai, Shuhei Morita, Daisuke Okuzaki, Mika Kaku, Kanta Sawase, Takashi Kato, Takashi Orimo, Ko-ichi Furukawa, Tsuneyasu Kaisho
    • Organizer
      第28回日本免疫毒性学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] An endoplasmic reticulum stress sensor IRE1a is involved in cholera toxin-induced interleukin-1b production from resident peritoneal macrophages2021

    • Author(s)
      Izumi Sasaki, Yuri Fukuda-Ohta, Shuhei Morita, Daisuke Okuzaki, Takashi Kato, Takashi Orimo, Koichi Furukawa, Tsuneyasu Kaisho
    • Organizer
      The 50th Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2021 Annual Research Report
  • [Presentation] コレラ毒素による免疫アジュバント活性における小胞体ストレスセンサーIRE1αの機能的意義2021

    • Author(s)
      佐々木泉, 中井千尋, 大田有里, 西山奈央子, 森田修平, 奥崎大介, 三並桃佳, 林茉里, 張江伊水, 田中日向子, 加藤喬, 折茂貴是, 古川鋼一, 改正恒康
    • Organizer
      第25回日本がん免疫学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] The role of IRE1α in cholera toxin B-induced interleukine-1β production from resident peritoneal macrophages2021

    • Author(s)
      Izumi Sasaki, Chihiro Nakai, Shuhei Morita, Daisuke Okuzaki, Yuri Fukuda-Ohta, Takashi Orimo, Hiroaki Hemmi, Koichi Furukawa, Tsuneyasu Kaisho
    • Organizer
      MMCB2020+1 The 27th International Symposium on Molecular Cell Biology of Macrophages
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The roles of unfold protein responses in cholera toxin B-induced interleukine-1β production.2020

    • Author(s)
      Sasaki I, Orimo T, Harie I, Takisawa Y, Furukawa K, Kaisho T.
    • Organizer
      第27回日本免疫毒性学会学術年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 自然免疫応答における小胞体ストレスセンサーIRE1αの 機能的意義2020

    • Author(s)
      三並桃佳、石田エヴァ如月、加藤喬、折茂貴是、大田(福田)有里、西山奈央子、中井千尋、佐々木泉、改正恒康
    • Organizer
      第88回和歌山医学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 遺伝性炎症性疾患COPA症候群の分子基盤の解明2020

    • Author(s)
      田中日向子、林茉里、加藤喬、折茂貴是、大田(福田)有里、西山奈央子、中井千尋、佐々木泉、改正恒康
    • Organizer
      第88回和歌山医学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 遺伝性炎症性疾患COPA症候群のモデルマウスの樹立とその解析2020

    • Author(s)
      張江伊水、滝沢優子、加藤喬、折茂貴是、大田(福田)有里、西山奈央子、中井千尋、佐々木泉、改正恒康
    • Organizer
      第88回和歌山医学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Cholera toxin B can induce interleukine-1β production in peritoneal macrophages through the pyrin inflammasome as well as the NLRP3 inflammasome.2019

    • Author(s)
      Sasaki I, Orimo T, Hemmi H, Furukawa K, Kaisho T.
    • Organizer
      第26回マクロファージ分子細胞生物学国際シンポジウム
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Analysis of mice carrying a novel and missense mutation of proteasome subunit gene identified in a patient with autoinflammation and immune deficiency.2019

    • Author(s)
      Hemmi H, Orimo T, Nishiyama N, Kato T, Ozasa T, Sasaki I, Kinjo N, Kanazawa N, Kaisho T.
    • Organizer
      第26回マクロファージ分子細胞生物学国際シンポジウム
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] コレラ毒素Bサブユニットは細胞内病原体センサーNLRP3とPyrinを介して炎症性サイトカインIL-1βの産生を誘導する2019

    • Author(s)
      佐々木泉、折茂貴是、邊見弘明、古川鋼一、改正恒康
    • Organizer
      第29回日本樹状細胞研究会
    • Related Report
      2019 Research-status Report
  • [Presentation] ヒト疾患由来プロテアソームサブユニット突然変異導入マウスにおける樹状細胞分化障害.2019

    • Author(s)
      邊見弘明、小笹俊哉、加藤喬、折茂貴是、佐々木泉、大田(福田)有里、金澤伸雄、改正恒康.
    • Organizer
      第29回日本樹状細胞研究会
    • Related Report
      2019 Research-status Report
  • [Presentation] コレラ毒素Bサブユニットとリポ多糖による相乗的なIL-1β産生誘導機構2019

    • Author(s)
      佐々木泉
    • Organizer
      第28回内毒素・LPS研究会
    • Related Report
      2019 Research-status Report
  • [Presentation] コレラ毒素Bサブユニットによる炎症性サイトカインIL-1β産生誘導機構2019

    • Author(s)
      佐々木泉、折茂貴是、邊見弘明、土屋慧馬、井上正一、熊谷直光、古川鋼一、改正恒康
    • Organizer
      第26回日本免疫毒性学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Cholera toxin B can induce interleukine-1β production in peritoneal macrophages through the pyrin inflammasome as well as the NLRP3 inflammasome.2019

    • Author(s)
      Sasaki I, Orimo T, Hemmi H, Furukawa K, Kaisho T.
    • Organizer
      The 18th Awaji International Forum on Infection and Immunity
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Roles of endoplasmic reticulum stress in cholera toxin B-induced interleukine-1β production from resident peritoneal macrophages.2019

    • Author(s)
      Sasaki I, Morita S, Okuzaki D, Orimo T, Hemmi H, Furukawa K, Kaisho T.
    • Organizer
      第48回日本免疫学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Defective dendritic cell and monocyte development in proteasome subunit mutant mice.2019

    • Author(s)
      23.Hemmi H, Orimo T, Sasaki I, Kato T, Fukuda-Ohta Y, Kinjo N, Hamada S, Kinoshita A, Yoshiura KI, Ohnishi H, Kanazawa N, Kaisho T.
    • Organizer
      第48回日本免疫学会学術集会
    • Related Report
      2019 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2023-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi