The role of unfolded protein responses in cholera toxin-induced immune adjuvant effect
Project/Area Number |
19K07628
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49070:Immunology-related
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Research Institution | Wakayama 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)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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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)
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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。
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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.
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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。
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Report
(4 results)
Research Products
(26 results)
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[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
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Journal Title
Nature Communications
Volume: 12
Issue: 1
Pages: 0-0
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
Arthritis & Rheumatology
Volume: in press
Issue: 11
Pages: 2105-2115
DOI
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Peer Reviewed / Open Access
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[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.
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Journal Title
British Journal of Cancer
Volume: 122
Issue: 8
Pages: 1185-1193
DOI
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Peer Reviewed / Open Access
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[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.
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Journal Title
Biochem Biophys Res Commun.
Volume: 30;525
Issue: 2
Pages: 477-482
DOI
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Peer Reviewed / Open Access
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[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
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Journal Title
International Journal of Hematology
Volume: 印刷中
Issue: 6
Pages: 744-750
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
International Immunology
Volume: 印刷中
Issue: 10
Pages: 657-668
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Cancer Science
Volume: 110
Issue: 4
Pages: 1279-1292
DOI
Related Report
Peer Reviewed / Open Access
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[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
Int'l Joint Research
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[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
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[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
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[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
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