A novel role for EBI3, a common subunit of IL-27 and IL-35, as a intracellular molecule in the augmentation of IL-23Ra protein expression

• Project/Area Number: 15K07947
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo Medical University
• Principal Investigator: Mizoguchi Izuru 東京医科大学, 医学部, 講師 (00569527)
• Co-Investigator(Kenkyū-buntansha): 善本 隆之 東京医科大学, 医学部, 教授 (80202406)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: EBI3 / IL-23Ra / カルネキシン / IL-23R / 腸炎

Outline of Final Research Achievements

We explored an intracellular role of Epstein-Barr virus-induced gene 3 (EBI3) independent of function as cytokines. EBI3-deficient naive CD4+ T cells had reduced interferon (IFN)-γ production and failed to induce T cell-dependent colitis in mice. Similarly reduced IFN-γ production was observed in vitro in EBI3-deficient CD4+ T cells differentiated under pathogenic helper T 17 polarizing conditions with IL-23 because of decreased expression of IL-23 receptor α (IL-23Rα) at the protein level but not the mRNA level. EBI3 augmented IL-23Rα expression via binding to the chaperone molecule calnexin and to IL-23Rα. However, EBI3 poorly augmented the expression of G149R, an IL-23Rα variant that protects against the development of human colitis, because binding of EBI3 to the variant was significantly reduced. These results suggest that EBI3 plays a critical role in augmenting IL-23Rα protein expression via calnexin under inflammatory conditions.

Research Products

• [Int'l Joint Research] Merck Research Laboratories(米国)
• [Journal Article] Interleukin-27 exerts its antitumor effects by promoting differentiation of hematopoietic stem cells to M1 macrophages. (2018)
  • Author(s): Chiba Y, Mizoguchi I, Furusawa J, Hasegawa H, Ohashi M, Xu M, Owaki T, Yoshimoto T.
  • Journal Title: Cancer Res. Volume: 78 Issue: 1 Pages: 182-194
  • DOI: 10.1158/0008-5472.can-17-0960
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of myelopoiesis by proinflammatory cytokines in infectious diseases. (2018)
  • Author(s): Chiba Y, Mizoguchi I, Hasegawa H, Ohashi M, Orii N, Nagai T, Sugahara M, Miyamoto Y, Xu M, Owaki T, Yoshimoto T.
  • Journal Title: Cell. Mol. Life Sci. Volume: 75 Issue: 8 Pages: 1363-1376
  • DOI: 10.1007/s00018-017-2724-5
  • Peer Reviewed / Open Access
• [Journal Article] Protective effects against tumors and infection by IL-27 through promotion of expansion and differentiation of hematopoietic stem cells into myeloid progenitors. (2018)
  • Author(s): Orii N, Mizoguchi I, Chiba Y, Hasegawa H, Ohashi M, Xu M, Nagai T, Ochiai M, Mochizuki Y, Owaki T, Yoshimoto T.
  • Journal Title: Oncoimmunology Volume: - Issue: 5 Pages: e1421892-e1421892
  • DOI: 10.1080/2162402x.2017.1421892
  • Peer Reviewed
• [Journal Article] Prediction of chemical respiratory and contact sensitizers by OX40L expression in dendritic cells using a novel 3D co-culture system. (2017)
  • Author(s): Mizoguchi I, Ohashi M, Chiba Y, Hasegawa H, Xu M, Owaki T, Yoshimoto T.
  • Journal Title: Front. Immunol. Volume: 8 Pages: 929-929
  • DOI: 10.3389/fimmu.2017.00929
  • Peer Reviewed / Open Access
• [Journal Article] Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family (2016)
  • Author(s): Hasegawa Hideaki, Izuru Mizoguchi, Yukino Chiba, Mio Ohashi, Mingli Xu, and Takayuki Yoshimoto
  • Journal Title: Frontires in Immunolgy Volume: -
  • DOI: 10.3389/fimmu.2016.00479
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression. (2016)
  • Author(s): Kimura Y, Nagai N, Tsunekawa N, Sato-Matsushita M, Yoshimoto T, Cua DJ, Iwakura Y, Yagita H, Okada F, Tahara H, Saiki I, Irimura T, Hayakawa Y.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 9 Pages: 1206-14
  • DOI: 10.1111/cas.13005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expansion and differentiation of hematopoietic stem cells by IL-27 into myeloid progenitors to control infection (2016)
  • Author(s): Furusawa J-I, Mizoguchi I, Chiba Y, Hisada M, Kobayashi F, Yoshida H, Nakae S, Tshuchida A, Matsumoto T, Ema H, Mizuguchi J, Yoshimoto T
  • Journal Title: PLoS Pathogen Volume: 12 Issue: 3 Pages: e1005507-e1005507
  • DOI: 10.1371/journal.ppat.1005507
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic potential of interleukin-27 against cancers in preclinical mouse models. (2015)
  • Author(s): Mizoguchi, I., Chiba, Y., Furusawa, J., Xu, M., Tsunoda, R., Higuchi, K., and Yoshimoto,
  • Journal Title: Oncoimmunology Volume: 4(10) Issue: 10 Pages: e1042200-e1042200
  • DOI: 10.1080/2162402x.2015.1042200
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Potential clinical application of interleukin-27 as an antitumor agent. (2015)
  • Author(s): Yoshimoto, T., Chiba, Y., Furusawa, J., Xu, M., Tsunoda, R., Higuchi, K., and Mizoguchi, I.
  • Journal Title: Cancer Sci. Volume: 106(9) Issue: 9 Pages: 1103-1110
  • DOI: 10.1111/cas.12731
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] A novel role for EBI3 to augment IL-23Rα protein expression through a lectin chaperone calnexin. (2018)
  • Author(s): Mizoguchi, I., Ohashi, M., Hasegawa, H., Chiba, Y., Orii, N., Kan, S., Xu, M., Ochiai, N., Owaki, T., and Yoshimoto, T.
  • Organizer: 東京医科大学記念館ポスター発表懇談会
• [Presentation] A novel antitumor activity of IL-27 by promoting the differentiation of HSCs to antitumorigenic M1-like macrophages in tumor-bearing mice. (2017)
  • Author(s): Chiba, Y., Ohashi, M., Hasegawa, H., Xu, M., Owaki, T., Mizoguchi, I., and Yoshimoto, T.
  • Organizer: The 2nd International Conference on Cytokine Signaling in Cancer
  • Int'l Joint Research
• [Presentation] IL-27/IL-35共通サブユニットEBI3によるIL-23Rの新しい蛋白質発現安定化機構 (2017)
  • Author(s): 溝口出、千葉祐規乃、長谷川英哲、大橋美緒、中村涼乃、折井直子、干詩宇、徐明利、大脇敏之、善本隆之
  • Organizer: 第6回医薬工3大学包括連携推進シンポジウム
• [Presentation] A novel role for Epstein-Barr virus-induced gene 3 to augment IL-23 receptor α protein expression through a lectin chaperone calnexin. (2017)
  • Author(s): Mizoguchi, I., Ohashi, M., Hasegawa, H., Chiba, Y., Xu, M., and Yoshimoto, T.
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] 炎症時の新しい蛋白質発現の増強機構 (2017)
  • Author(s): 溝口 出
  • Organizer: Annual Meeting 2017医学総合研究所 研究発表会
• [Presentation] Development of a novel 3D co-culture system for evaluation of respiratory sensitizing potential. (2016)
  • Author(s): Ohashi, M., Mizoguchi, I., Hasegawa, H., Chiba, C., Xu, M., and Yoshimoto, T.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] A pivotal role for IL-23p19 produced by activated CD4+ T cells in development of EAE. (2016)
  • Author(s): Hasegawa, H., Mizoguchi, I., Chiba, Ohashi, M., C., Xu, M., and Yoshimoto, T.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] IL-27 induces antitumor activity by promoting differentiation of HSCs to M1-like antitumorigenic macrophages and their mobiliziation into tumor. (2016)
  • Author(s): Chiba, Y., Mizoguchi, I., Hasegawa, H., Ohashi, M., C., Xu, M., and Yoshimoto, T.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄
  • Year and Date: 2016-12-05
• [Presentation] Promotion of expansion and differentiation of hematopoietic stem cells by IL-27 into myeloid progenitors to control infection in emergency myelopoiesis. (2016)
  • Author(s): Yoshimoto, T., Furusawa, J., Chiba, Y., Xu, M., Hasegawa, H., Nakae, S., Kobayashi, F., Yoshida, H., and Mizoguchi, I. Ohashi, M., Hasegawa, H., and Mizoguchi, I.
  • Organizer: Symposium, 16th International Congress of Immunology
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21
• [Presentation] アレルギー感作性をin vitroで評価する新しい方法の開発 (2016)
  • Author(s): 溝口出、大橋美緒、長谷川英哲、千葉祐規乃、徐明利、善本隆之
  • Organizer: 第5回医薬工3大学包括連携推進シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2016-06-18
• [Presentation] 化学物質の呼吸器感作性in vitro評価法の開発 (2015)
  • Author(s): 善本隆之、千葉佑規乃、角田廉、徐明利、溝口出
  • Organizer: 第28回日本動物実験代替法学会
  • Place of Presentation: 横浜
  • Year and Date: 2015-12-10
  • Invited
• [Presentation] Binding of Epstein-Barr virus-induced gene 3 to calnexin enhances its chaperone activity and augments interleukin-23 receptor expression, leading to development of colitis. (2015)
  • Author(s): Mzoguchi, I., Chiba, Y., Xu, M., and Yoshimoto, T.
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] 慢性骨髄性白血病患者における治療中止を成功させるための予測因子 (2015)
  • Author(s): 片桐誠一朗、田内哲三、梅津知宏、田所健一、溝口出、善本隆之、大屋敷純子、大屋敷一馬
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Stop-imatinib CML患者末梢血単核球における免疫関連miRNAの意義 (2015)
  • Author(s): 大屋敷一馬、溝口出、善本隆之、田内哲三、岡部聖一、片桐誠一朗、梅津知宏、大屋敷純子
  • Organizer: 第7回血液疾患免疫療法研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-26
• [Presentation] 化学物質の呼吸器感作性in vitro評価法の開発 (2015)
  • Author(s): 溝口出、千葉佑規乃、角田廉、徐明利、善本隆之
  • Organizer: 第3期LRI研究報告会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-28