Study on the regulation of immune responses by a novel IL-6/IL-12 family cytokine

• Project/Area Number: 24370058
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Tokyo Medical University
• Principal Investigator: YOSHIMOTO Takayuki 東京医科大学, 医学部, 教授 (80202406)
• Co-Investigator(Kenkyū-buntansha): NAKAE Susumu 東京大学, 医科学研究所, 准教授 (60450409)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: EBI3 / IL-27 / p19 / IL-23R / IL-23 / IL-23p19 / EAE

Outline of Final Research Achievements

In the present study, we found that activated CD4+ T cells secreted p19 and EBI3, and that forced expression of them in cultured cells showed association of them. Moreover, injection of expression vector of EBI3/p19 into mice augmented IL-17 production, and transgenic mice of EBI3/p19 showed increased resistance to the development of autoimmune hepatitis possibly due to enhanced production of IL-22. Taken together, these results suggested that EBI3/p19 may be a novel functional heterodimeric molecule.

Research Products

• [Journal Article] Intratumoral CD4+ T lymphodepletion sensitizes poorly immunogenic melanomas to immunotherapy with an OX40 agonist. (2014)
  • Author(s): Fujiwara, S., Nagai, H., Shimoura, N., Oniki, S., Yoshimoto, T., and Nishigori, C.
  • Journal Title: Journal of Investigative Dermatology Volume: 134 Pages: 1884-1892
  • DOI: 10.1038/jid.2014.42
  • Peer Reviewed
• [Journal Article] Contribution of IL-12/IL-35 common subunit p35 to maintaining the testicular immune privilege (2014)
  • Author(s): Terayama H, Yoshimoto T, Hirai S, Naito M, Qu N, Hatayama N, Hayashi S, Mitobe K, Furusawa J, Mizoguchi I, Kezuka T, Goto H, Suyama K, Moriyama H, Sakabe K, Itoh M.
  • Journal Title: PLoS One Volume: 9
  • DOI: 10.1371/journal.pone.0096120
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Immunosurveillance markers may predict patients who can discontinue imatinib therapy without relapse. (2014)
  • Author(s): Yoshimoto, T., Mizoguchi, I., Katagiri, S., Tauchi, T., Furusawa, J., Chiba, Y., Mizuguchi, J., Ohyashiki, J. H., and Ohyashiki, K.
  • Journal Title: Oncoimmunology Volume: 3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Down-regulated microRNA-148b in circulating PBMCs in chronic myeloid leukemia patients with undetectable minimal residual disease: A possible molecular classifier to stop imatinib safely. (2014)
  • Author(s): Ohyashiki, J. H., Ohtsuki, K., Mizoguchi, I., Yoshimoto, T., Katagiri, S., Umezu, T., and Ohyashiki, K.
  • Journal Title: Drug Des Devel Ther. Volume: 8 Pages: 1151-1159
  • DOI: 10.2147/dddt.s66812
  • Peer Reviewed / Open Access
• [Journal Article] Immunological control of chronic myeloid leukemia leading to treatment-free remission. (2014)
  • Author(s): Mizoguchi, I., Yoshimoto, T., Katagiri, S., Furusawa, J., Chiba, Y., Mizuguchi, J., Tauchi, T., Ohyashiki, J. H., and Ohyashiki, K.
  • Journal Title: J. Hematol. Transfus. Volume: 2(3) Pages: 1024-1024
  • Peer Reviewed / Open Access
• [Journal Article] The ARNT-STAT axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+cells. (2014)
  • Author(s): Nakajima K, Maekawa K, Kataoka K, Ishifune C, Nishida J, Arimochi H, Yoshimoto T, Tomita S, Nagahiro S, Yasutomo K.
  • Journal Title: Nat Communications Volume: 4 Pages: 1-11
  • DOI: 10.1038/ncomms3112
  • Peer Reviewed
• [Journal Article] IL-27 promotes nitric oxide production induced by LPS through STAT1, NF-kB and MAPKs (2013)
  • Author(s): Shimizu, et al.
  • Journal Title: Immunobiology Volume: 218 Pages: 628-634
  • DOI: 10.1016/j.imbio.2012.07.028
  • Peer Reviewed
• [Journal Article] Sustained up-regulation of effector natural killer cells in chronic myeloid leukemia after discontinuation of imatinib. (2013)
  • Author(s): Mizoguchi, I., Yoshimoto, T., Katagiri, S., Mizuguchi, J., Tauchi, T., Kimura, Y., Inokuchi, K., Ohyashiki, J. H., and Ohyashiki, K.
  • Journal Title: Cancer Sci. Volume: 104 Pages: 1146-1153
  • DOI: 10.1111/cas.12216
  • Peer Reviewed
• [Journal Article] Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases. (2013)
  • Author(s): Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K, Mizuguchi J, Itoh M,Kawakami Y, Yoshimoto T.
  • Journal Title: Clin Dev Immunol Volume: 2013:968549 Pages: 1-13
  • DOI: 10.1155/2013/968549
  • Peer Reviewed
• [Journal Article] IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperating with a TLR3 agonist poly(I:C) partly in TRAIL-dependent manner (2013)
  • Author(s): Chiba Y, Mizoguchi K, Mitobe I, Higuchi K, Nagai H, Nishigori C, Mizuguchi J, Yoshimoto T
  • Journal Title: PLoS One Volume: 8(10)
  • DOI: 10.1371/journal.pone.0076159
  • Peer Reviewed
• [Journal Article] Epitherlial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma (2012)
  • Author(s): Suzukawa, et al.
  • Journal Title: J. Immunol. Volume: 189 Pages: 3641-3652
  • Peer Reviewed
• [Journal Article] Identification of a novel role of Septin 10 in Paclitaxel-resistance in cancers through a functional genomics screen (2012)
  • Author(s): Xu M, Takanashi M, Oikawa K, Nishi H, Isaka K, Yoshimoto T, Ohyashiki J, Kuroda M
  • Journal Title: Cancer Science Volume: 103 Pages: 821-7
  • DOI: 10.1111/j.1349-7006.2012.02221.x
  • Peer Reviewed
• [Journal Article] Interleukin(IL)-17 versus IL-27: Opposite effects on tumor necrosis factor-alpha-mediated chemokine production in human keratinocytes (2012)
  • Author(s): S. Fujiwara, H. Nagai, S. Oniki, T. Yoshimoto, and C. Nishigori
  • Journal Title: Exp. Dermatol. Volume: 21 Pages: 70-72
  • DOI: 10.1111/j.1600-0625.2011.01384.x
  • Peer Reviewed
• [Presentation] IL-27 exerts potent antitumor activity by promoting the differentiation of hematopoietic stem cells to M1-like antitumor macrophages and their mobilization. (2014)
  • Author(s): Chiba, Y., Furusawa, J., Mizoguchi, I., Xu, M., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] IL-27 promotes the differentiation of hematopoietic stem cells into multipotent myeloid progenitor cells. (2014)
  • Author(s): Furusawa, J., Chiba, Y., Mizoguchi, I., Xu, M., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] PepTivator® OVA-pulsed DCs can induce both OVA specific CD8+ and CD4+ T cells in mouse model. (2014)
  • Author(s): Miki, K., Nagaoka, K., Yoshimoto, T., Kamigaki, T. and Maekawa, R.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulation of antitumor immune responses through differentiation and mobilization of hematopoietic stem cells by IL-27. (2014)
  • Author(s): Chiba, Y., Mizoguchi, I., Hisada, M., Tsuchida, A., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] IL-27 promotes the differentiation of hematopoietic stem cells into DC progenitor cells. (2014)
  • Author(s): Furusawa, J., Chiba, Y., Mitobe, K., Mizoguchi, I., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 13th International Symposium on Dendritic Cells, DC2014
  • Place of Presentation: Tours, France
  • Year and Date: 2014-09-14 – 2014-09-18
• [Presentation] Contribution of IL-35 to maintaining the testicular immune privilege. (2014)
  • Author(s): Terayama, H., Naito, M., Yoshimoto, T., Hirai, S., Qu, N., Kuramasu, M., Hatayama, N., Kanazawa, T., Suyama, K., Sakabe, K., and Itoh, M.
  • Organizer: 第33回日本アンドロロジー学会学術大会
  • Place of Presentation: 軽井沢
  • Year and Date: 2014-06-12 – 2014-06-13
• [Presentation] Induction of antigen specific T cells using PepTivator®-pulsed DCs. (2014)
  • Author(s): Takahara, M., Goto, S., Miki, K., Saiwaki, S., Nagaoka, K., Matsushita, H., Kondo, T. Bohnenkamp, H., Yoshimoto, T., Maekawa, R., and Kamigaki, T.
  • Organizer: International Society For Cellular Therapy 20th Annual Meeting 2014
  • Place of Presentation: Paris, France
  • Year and Date: 2014-04-23 – 2014-04-26
• [Presentation] Induction of both OVA specific CD4+ and CD8+ T cells by using PepTivator® OVA-pulsed DCs in mouse model. (2014)
  • Author(s): Miki, K., Nagaoka, K., Bohnenkamp, H., Yoshimoto, T., Kamigaki, T. and Maekawa, R.
  • Organizer: American Association for Cancer Research 105th Annual Meeting 2014
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] EBI3 functions as an intracellular molecule to regulate the development of colitis in naive CD4+CD25- T cells. (2013)
  • Author(s): Mizoguchi, I. Mitobe, K., Tsunoda, R., Higuchi, K., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第78日本インターフェロン・サイトカイン学会総会(JSICR)/第21回マクロファージ分子細胞生物国際シンポジウム(MMCB)合同学術集会
  • Place of Presentation: 東京
• [Presentation] The percentage of effector populations of NK cells correlated highly with sustained CMR with or without imatinib in chronic myeloid leukemia patients. (2013)
  • Author(s): Katagiri, S., Mizoguchi, I., Yoshimoto, T., Mizuguchi, J., Ohyashiki, J.H., Tauchi, T., Inokuchi, K., and Ohyashiki, K.
  • Organizer: 18th Congress of the European Hematology Association
  • Place of Presentation: Stockholm, Sweden
• [Presentation] EBI3 functions as an intracellular molecule to regulate the development of colitis in naive CD4+CD25- T cells. (2013)
  • Author(s): Mizoguchi, I. Mitobe, K., Tsunoda, R., Higuchi, K., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy,
• [Presentation] New approach for DC-mediated cancer vaccine using IL-27-expanded myeloid progenitor cells. (2013)
  • Author(s): Yoshimoto, T., Mizoguchi, I. Hisada, M., and Mizuguchi, J.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] EBI3 promotes IL-23-mediated signaling resulting in the development of colitis by enhancing IFN-g production. (2013)
  • Author(s): Mizoguchi, I., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第42回日本免疫学会総会
  • Place of Presentation: 千葉
• [Presentation] Activation levels of NK and CD8^+ T cells correlate with sustained CMR after discontinuation of imatinib in CML patients (2012)
  • Author(s): Yoshimoto, et al.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-21
• [Presentation] Cooperative growth inhibition of human melanomas by IL-27 and a TLR3 agonist poiy(I : C) in TRAIL-dependent manner (2012)
  • Author(s): Mizoguchi, et al.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-21
• [Presentation] Dendritic cells loaded with antigen by electroporation induce strong anti-tumor immunity in vivo (2012)
  • Author(s): Nagaoka, et al.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-21
• [Presentation] Role of intratesticular Epstein-Barr virus-induced genen-3 (EB13) in the mouse (2012)
  • Author(s): Terayama, et al.
  • Organizer: The Japan Society of Andrology The 31^<st> Annual Meeting & The 18^<th> Japanese Testis Workshop
  • Place of Presentation: Kobe, Japan
• [Presentation] Comparison of antigen-loading methods into dendritic cells with protein, mRNA or peptides derived ovalbumin for antigen presenting activity (2012)
  • Author(s): Nagaoka, et al.
  • Organizer: The 12th International Symposium on Dendritic Cells
  • Place of Presentation: Daegu, Korea
• [Presentation] Aryl hydrocarbon receptor nuclear translocator as a regulator of the differentiation of intestinal intraepithelial CD8αα T cells (2012)
  • Author(s): Nakajima, et al.
  • Organizer: 第41回日本免疫学会総会
  • Place of Presentation: 神戸
• [Presentation] EBI3 functions as an adaptor molecule associating with p62/SQSTM1 to regulate the development of colitis in CD4^+ T cells (2012)
  • Author(s): Mizoguchi, et al.
  • Organizer: 第41回日本免疫学会総会
  • Place of Presentation: 神戸
• [Presentation] Induction of nitric oxide by macrophages stimulated with IL-27 and lipopolysaccaride through STAT1,NF-kB and MAPKs (2012)
  • Author(s): Shimizu, et al.
  • Organizer: 第41回日本免疫学会総会
  • Place of Presentation: 神戸
• [Presentation] EBI3 (Epstein-Barr virus-induced gene-3) ノックアウトマウスにおける精巣免疫微小環境について (2012)
  • Author(s): 寺山隼人, 他
  • Organizer: 第27回日本生殖免疫学会総会・学術集会
  • Place of Presentation: 大阪
• [Presentation] Activation levels of natural killer cells and CD8^+ T cells correlate highly with sustained complete molecular response after discontinuation of imatinib in chronic myeloid leukemia patients (2012)
  • Author(s): Katagiri, et al.
  • Organizer: 2012 ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta GA, USA
• [Book] Cytokine Frontiers: Regulation of Immune Responses in Health and Disease. (2013)
  • Author(s): Yoshimoto, T. and Yoshimoto, T. (Editors)
  • Total Pages: 396
  • Publisher: Springer
• [Remarks]