Identification and functional analysis of a novel IL-6/IL-12 family cytokine

• Project/Area Number: 15K08433
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tokyo Medical University
• Principal Investigator: Xu Mingli 東京医科大学, 医学部, 客員講師 (80597964)
• 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 / p19 / heterodimeric cytokine / IL-27 / IL-23

Outline of Final Research Achievements

In the present study, we elucidated that Epstein-Barr virus-induced gene 3 (EBI3), a common subunit of IL-27 and IL-35, and p19, one of IL-23 subunits can form a functional heterodimeric cytokine. EBI3 was first revealed to associate with p19, and subsequently hydrodynamic injection of the expression vector of a single chain of EBI3/p19 into mice was shown to augment an antigen-specific production of cytokines such as IL-17 and granulocyte-macrophage colony-stimulating factor in the draining lymph node cells. Then, transgenic mice over expressing the single chain of EBI3/p19 were established and exhibited resistance to the development of autoimmune hepatitis induced by injection with concanavalin A. Moreover, using a transplantable mouse tumor model of melanoma B16F10, EBI3/p19 was demonstrated to show potent antitumor activity. Currently, more detailed analysis on the molecular mechanism and its physiological role is under investigation.

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 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] 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] Prediction of chemical respiratory and contact sensitizers by OX40L expression in dendritic cells using a novel 3D co-culture system. (2017)
  • Author(s): Ohashi, M., Mizoguchi, I., Chiba, Y., Hasegawa, H., Xu, M., and Yoshimoto, T.
  • Organizer: 第46回日本免疫学会総会・学術集会
• [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
  • Int'l Joint Research
• [Presentation] Establishment of a novel in vitro evaluation system for the prediction of respiratory sensitizing potential of chemicals. (2016)
  • Author(s): Yoshimoto, T., Ohashi, M., Hasegawa, H., Chiba, Y., Xu, M., and Mizoguchi, I.
  • Organizer: ICCA-LRI and NIHS Workshop
  • Place of Presentation: Awaji Island
  • Year and Date: 2016-06-15
  • Int'l Joint Research
• [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): Mizoguchi, 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] 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