Regulation of immune responses by IL-23 p19, IL-27 EBI3 or their new heterodimer

• Project/Area Number: 24790091
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Tokyo Medical University
• Principal Investigator: MIZOGUCHI Izuru 東京医科大学, 医学部, 助教 (00569527)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IL-27 / EBI3 / 腸炎 / IL-23R / IL-23レセプター / オートファジー / Colitis

Outline of Final Research Achievements

In the present study, we found that the common subunit, EBI3, between the IL-6/IL-12 family cytokines IL-27 and IL-35 plays a novel role as an intracellular molecule in IL-27/IL-35-independent manner. Namely, EBI3 was presumably demonstrated to associate with the scaffold protein p62/SQSTM1, which plays a critical role in the degradation of ubiqutinated protein by autophagy, and therefore inhibit the degradation of ubiqutinated IL-23 receptor, possibly resulting in induction of colitis by augmentation of IL-23 signaling.

Research Products

• [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 Issue: 4 Pages: e96120-e96120
  • 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 / Acknowledgement Compliant
• [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 Issue: 4 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 Issue: 9 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) Issue: 10 Pages: e76159-e76159
  • DOI: 10.1371/journal.pone.0076159
  • Peer Reviewed
• [Journal Article] サイトカインのすべて IL-27 (2012)
  • Author(s): 千葉祐規乃 他
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57 Pages: 172-183
• [Journal Article] サイトカインのすべて IL-30 (2012)
  • Author(s): 溝口出 他
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57 Pages: 188-196
• [Journal Article] DCワクチンをリンパ節投与した際の局所滞留性と免疫誘導能の検討 (2012)
  • Author(s): 太田裕士 他
  • Journal Title: 東京医科大学雑誌 Volume: 70 Pages: 444-449
• [Journal Article] 抑制性サイトカインIL-10とIL-35による免疫反応の恒常性の維持 (2012)
  • Author(s): 溝口出 他
  • Journal Title: 細胞工学 Volume: 31 Pages: 765-771
• [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] 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] 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] 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] 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: 幕張
• [Presentation] Activation levels of NK and CD8+ T cells correlate with sustained CMR after discontinuation of imatinib in CML patients. (2012)
  • Author(s): Yoshimotet et al.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Cooperative growth inhibition of human melanomas by IL-27 and a TLR3 agonist poly(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
• [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-κB 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] 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
• [Presentation] Up-regulation of effector natural killer cells and effector memory CD8+ T cells in maintaining complete molecular response after imatinib discontinuation in chronic myeloid leukemia.
  • Author(s): 溝口出、片桐誠一朗、水口純一郎、大屋敷純子、大屋敷一馬、善本隆之
  • Organizer: 第171回東京医科大学医学会総会
  • Place of Presentation: 東京
• [Presentation] IL-27とPoly(I:C)による協調的TRAILとTLR3発現増強を介したメラノーマ腫瘍増殖のTRAIL依存的抑制
  • Author(s): 溝口出 他
  • Organizer: 第87回東京医科大学・東京薬科大学・免疫アレルギー研究会
  • Place of Presentation: 東京
• [Presentation] CD4陽性T細胞から産生されるIL-12ファミリーサイトカイン構成因子EBI3の炎症性腸疾患発症への関与
  • Author(s): 溝口出 他
  • Organizer: 第169回東京医科大学医学会総会
  • Place of Presentation: 東京
• [Presentation] 接触性皮膚炎のメカニズム解明～IL-27およびIL-35の共通のサブユニットEBI3の新たな役割～
  • Author(s): 松本龍門 他
  • Organizer: 第170回東京医科大学医学会総会
  • Place of Presentation: 東京