New mechanism whereby IL-23 regulates immune responses through Notch signalling

• Project/Area Number: 23590475
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Keio University (2012-2013); Tokyo Medical University (2011)
• Principal Investigator: XU Mingli 慶應義塾大学, 医学部, 助教 (80597964)
• Co-Investigator(Kenkyū-buntansha): YOSHIMOTO Takayuki 東京医科大学, 医学部, 教授 (80202406) ; SUDO Katsuko 東京医科大学, 医学部, 講師 (50126091)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: IL-23 / IL-22 / IL-17 / Notch

Research Abstract

IL-23 is an important cytokine for maintenance of inflammatory Th17 cells. Using autoimmune hepatitis mouse model, endogenous IL-23 was demonstrated to induce IL-22-mediated protection from hepatitis, whereas exogenous IL-23 failed to protect from it because of the production of inflammatory cytokines such as IL-17 in addition to IL-22. Moreover, in a tumor model, endogenous IL-23 was revealed to promote the tumor growth via enhancing inflammation through augmentation of IL-17 production. On the other hand, exogenous IL-23 turned out to suppress the tumor growth.

Research Products

• [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] Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes (2013)
  • Author(s): Yoon JH, Jung SM, Park SH, Kato M, Yamashita T, Lee IK, Sudo K, Nakae S, Han JS, Kim OH, Oh BC, Sumida T, Kuroda M, Ju JH, Jung KC, Park SH, Kim DK, Mamura M
  • Journal Title: EMBO Mol Med Volume: 5(11) Pages: 1720-1739
  • Peer Reviewed
• [Journal Article] Heligmosomoides polygyrus infection reduces severity of type 1 diabetes induced by multiple low-dose streptozotocin in mice via STAT6- and IL-10-independent mechanisms (2013)
  • Author(s): Osada Y, Yamada S, Nabeshima A, Yamagishi Y, Ishiwata K, Nakae S, Sudo K, Kanazawa T
  • Journal Title: Exp Parasitol Volume: 135(2) Pages: 388-396
  • Peer Reviewed
• [Journal Article] Requirement of apoptosis-inducing kinase 1 for the induction of bronchial asthma following stimulation with ovalbumin (2013)
  • Author(s): Takada E, Furuhata M, Nakae S, Ichijo H, Sudo K, Mizuguchi J
  • Journal Title: Int Arch Allergy Immunol Volume: 162(2) Pages: 104-114
  • Peer Reviewed
• [Journal Article] IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation (2013)
  • Author(s): Kamijo S, Takeda H, Tokura T, Suzuki M, Inui K, Hara M, Matsuda H, Matsuda A, Oboki K, Ohno T, Saito H, Nakae S, Sudo K, Suto H, Ichikawa S, Ogawa H, Okumura K, Takai T
  • Journal Title: J Immunol Volume: 190(9) Pages: 4489-4499
  • 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] The ARNT-STAT axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+cells. (2013)
  • Author(s): Nakajima K, Maekawa K, Kataoka K, Ishifune C, Nishida J, Arimochi H, Yoshimoto T, Tomita S, Nagahiro S, Yasutomo K.
  • Journal Title: Nature Communications Volume: 4 Issue: 1 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 M, Ogura K, Mizoguchi I, Chiba Y, Higuchi K, Ohtsuka H, Mizuguchi J, Yoshimoto T
  • Journal Title: Immunobiology Volume: 218 Pages: 628-634
  • 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 Sci Volume: 103(4) Pages: 821-827
  • Peer Reviewed
• [Journal Article] Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma (2012)
  • Author(s): Suzukawa M, Morita H, Nambu A, Arae K, Shimura E, Shibui A, Yamaguchi S, Suzukawa K, Nakanishi W, Oboki K, Kajiwara N, Ohno T, Ishii A, Korner H, Cua DJ, Suto H, Yoshimoto T, Iwakura Y, Yamasoba T, Ohta K, Sudo K, Saito H, Okumura K, Broide DH, Matsumoto K, Nakae S
  • Journal Title: J Immunol Volume: 189(7) Pages: 3641-3652
  • Peer Reviewed
• [Journal Article] Th17 cell-derived IL-17 is dispensable for B cell antibody production (2012)
  • Author(s): Shibui A, Shimura E, Nambu A, Yamaguchi S, Leonard WJ, Okumura K, Sugano S, Sudo K, Nakae S
  • Journal Title: Cytokine Volume: 59(1) Pages: 108-114
  • Peer Reviewed
• [Journal Article] ST2 requires Th2-, but not Th17-, type airway inflammation in epicutaneously antigensensitized mice (2012)
  • Author(s): Morita H, Arae K, Ohno T, Kajiwara N, Oboki K, Matsuda A, Suto H, Okumura K, Sudo K, Takahashi T, Matsumoto K, Nakae S
  • Journal Title: Allergol Int Volume: 61(2) Pages: 265-273
  • NAID: 130004477129
  • Peer Reviewed
• [Journal Article] Interleukin (IL)-17 versus IL-27: opposite effects on TNF- -induced chemokine production in human keratinocytes (2012)
  • Author(s): Fujiwara, S., Nagai, H., Oniki, S., Yoshimoto, T. and Nishigori, C.
  • Journal Title: Exp. Dermatol Volume: 21 Pages: 70-72
  • Peer Reviewed
• [Journal Article] サイトカインのすべてIL-27 (2012)
  • Author(s): 千葉祐規乃、溝口出、森嶋紀子、徐明利、善本隆之
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57(Suppl.21) Pages: 172-183
• [Journal Article] がん免疫病態と免疫動態の評価 (2012)
  • Author(s): 河上裕、谷口智憲、中村公子、川瀬芳恵、野路しのぶ、大泉梓、南雲春菜、長谷川舞、徐明利、岡本正人、桜井敏晴、藤田知信
  • Journal Title: 血液フロンティア Volume: Vol.22,No.8 Pages: 1183-1190
• [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、徐明利、溝口出、高梨正勝、須藤カツ子、黒田雅彦、善本隆之、粕谷和彦、土田明彦、畝崎榮
  • Journal Title: 東京医科大学雑誌 Volume: 70(4) Pages: 444-449
  • NAID: 10031143025
  • Peer Reviewed
• [Journal Article] サイトカインのすべてIL-35 (2012)
  • Author(s): 徐明利、千葉祐規乃、善本隆之
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57(Suppl.21) Pages: 220-230
• [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 Sci Volume: 103 Issue: 4 Pages: 821-827
  • DOI: 10.1111/j.1349-7006.2012.02221.x
  • Peer Reviewed
• [Journal Article] サイトカインのすべて IL-27 (2012)
  • Author(s): 千葉祐規乃 等
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57 (Suppl. 21) Pages: 172-183
• [Journal Article] サイトカインのすべて IL-35 (2012)
  • Author(s): 徐明利 等
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57 (Suppl. 21) Pages: 220-230
• [Journal Article] がん免疫病態と免疫動態の評価 (2012)
  • Author(s): 河上裕 等
  • Journal Title: 血液フロンティア Volume: 22 Pages: 1183-1190
• [Journal Article] Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production (2011)
  • Author(s): Xu M, Morishima N, Mizoguchi I, Chiba Y, Fujita K, Kuroda M, Iwakura Y, Cua DJ, Yasutomo K, Mizuguchi J, Yoshimoto T
  • Journal Title: Eur J. Immunol Volume: 41 (10) Pages: 2828-2839
  • Peer Reviewed
• [Journal Article] Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion (2011)
  • Author(s): Itoh S, Kimura N, Axtell RC, Velotta JB, Gong Y, Wang X, Kajiwara N, Nambu A, Shimura E, Adachi H, Iwakura Y, Saito H, Okumura K, Sudo K, Steinman L, Robbins RC, Nakae S, Fischbein MP
  • Journal Title: Circulation Volume: 124(11 Suppl)
  • Peer Reviewed
• [Journal Article] Okumura K., Kamradt T., Saito H., Nakae S. Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage (2011)
  • Author(s): Ohno T., Oboki K., Kajiwara N., Tanaka S., Ikeda M., Iikura M., Akiyama T., Inoue J., Matsumoto K., Sudo K., Azuma M.,
  • Journal Title: Plos One Volume: 6 Issue: 4 Pages: 18404-18404
  • DOI: 10.1371/journal.pone.0018404
  • Peer Reviewed
• [Journal Article] Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells (2011)
  • Author(s): Meguro A, Ozaki K, Hatanaka K, Oh I, Sudo K, Ohmori T, Matsu H, Tatara R, Sato K, Sakata Y, Nakae S, Leonard WJ, Ozawa K
  • Journal Title: Bone Marrow Transplant Volume: 46(12) Pages: 1557-1565
  • Peer Reviewed
• [Journal Article] IL-23 gene therapy for mouse bladder tumor cell lines (2011)
  • Author(s): Kuramoto T, Fujii R, Nagai H, Belladonna ML, Yoshimoto T, Kohjimoto Y, Inagaki T, Hara I
  • Journal Title: BJU Int Volume: 108 Pages: 914-921
  • Peer Reviewed
• [Journal Article] Local expression of IL-27 ameliorates collagen induced arthritis (2011)
  • Author(s): Pickens SR, Volin MV, Mandelin II, AM, Matsui M, Yoshimoto T, Shahrara S
  • Journal Title: Arthritis Rheum Volume: 63 Pages: 2289-2298
  • Peer Reviewed
• [Journal Article] IL-27 suppresses RANKL expression in CD4+ T cells in part through STAT3 (2011)
  • Author(s): Kamiya S, Okumura M, Chiba Y, Nakamura C, Fukawa T, Nimura N, Mizuguchi J, Wada S, Yoshimoto T
  • Journal Title: Immunol. Let Volume: 138 Pages: 47-53
  • Peer Reviewed
• [Journal Article] IL-12、モデル動物利用マニュアル (2011)
  • Author(s): 奥村昌恵、徐明利、善本隆之
  • Journal Title: LIC Pages: 266-275
• [Journal Article] Regulation of the development of acute hepatitis (2011)
  • Author(s): Xu, M. et al.
  • Journal Title: Eur. J. Immunol. Volume: 41 Pages: 2828-2839
  • Peer Reviewed
• [Journal Article] IL-23 gene therapy (2011)
  • Author(s): Kuramoto, T. et al.
  • Journal Title: BJU Int. Volume: 108 Pages: 914-921
  • Peer Reviewed
• [Presentation] Strong correlation of tumor-infiltrating CD8^<+> and FOXP3^<+> T cells with favorable prognosis of patients with coloncancer (2013)
  • Author(s): Xu M, Noji S, Popivanova B, Okamoto M, Sakurai T, Fujita T, Torigoe T, Sato N, Sugiura F, Okuno K, Hazama S, Oka M, Kawakami Y
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ、千葉県
• [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, Yoshimoto, T
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy
• [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 JH, Tauchi T, Inokuchi K, Ohyashiki K
  • Organizer: 18th Congress of the European Hematology Association
  • Place of Presentation: Stockholm, Sweden
• [Presentation] Strong correlation of tumor-infiltrating CD8+ and FOXP3+ T cells with favorable prognosis of patients with colon cancer. (2013)
  • Author(s): Xu, M. et al.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Presentation] Cancer immune escalation process triggered by activation of γδT17 cells through MyD88/IL-23 cascade. (2013)
  • Author(s): Kimura, Y. et al.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Presentation] Cross-talk between host and cancer cells amplify inflammation triggered by γδT cells to promote malignant progression. (2013)
  • Author(s): Kimura, Y. et al.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] IL-27とPoly(1: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 (2012)
  • Author(s): 溝口出、千葉祐規乃、徐明利、樋口要、善本隆之、水口純一郎
  • 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
  • Year and Date: 2012-05-29
• [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 S, Mizoguchi I, Yoshimoto T, Mizuguchi J, Ohyashiki JH, Ohyashiki K
  • Organizer: 2012 ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta GA, USA
• [Presentation] Comparison of antigen-loading methods into dendritic cells with protein, mRNA or peptides derived ovalbumin for antigen presenting activity (2012)
  • Author(s): Nagaoka K, Miki K, Yoshimoto T, Kamigaki T, Maekawa R
  • Organizer: The 12th International Symposium on Dendritic Cells
  • Place of Presentation: Daegu, Korea
• [Presentation] 能動免疫療法における免疫誘導・抗腫瘍効果を規定するバイオマーカーの検索 (2012)
  • Author(s): 川瀬芳恵、藤田知信、大泉梓、野路しのぶ、桜井敏晴、南雲春菜、徐明利、中山一、垣見和宏、鳥越俊彦、池田裕明、珠玖洋、岡本正人、河上裕
  • Organizer: 第16回日本がん免疫学会総会
  • Place of Presentation: 札幌
• [Presentation] Efficient antigen presentation and induction of anti-tumor immunity by dendritic cells loaded with antigens by electroporation (2012)
  • Author(s): Nagaoka K, Takahara M, Yoshimoto T, Teruya T, Shiroma H, Maekawa R
  • Organizer: American Association of Cancer (AACR) Annual Meeting 2012
  • Place of Presentation: Chicago, IL, USA
• [Presentation] 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、徐明利、溝口出、高梨正勝、須藤カツ子、黒田雅彦、善本隆之、粕谷和彦、土田明彦、畝崎榮
  • Organizer: 第132年会日本薬学会
  • Place of Presentation: 札幌
• [Presentation] Role of intratesticular Epstein-Barr virus-induced genen-3 (EBI3) in the mouse (2012)
  • Author(s): Terayama H, Hirai S, Qu N, Hirayanagi Y, Musha M, Naito M, Yoshimoto T, Itoh M
  • Organizer: The Japan Society of Andrology The 31st Annual Meeting & The 18^<th> Japanese Testis Workshop
  • Place of Presentation: Kobe, Japan
• [Presentation] Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production (2011)
  • Author(s): Xu M, Morishima N, Mizoguchi I, Chiba Y, Fujita K, Kuroda M, Iwakura Y, Cua DJ, Yasutomo K, Mizuguchi J, Yoshimoto T
  • Organizer: 第168回東京医科大学医学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-05
• [Presentation] IL-27 enhances poly(I:C)-inducedapoptosisoftumorcells (2011)
  • Author(s): Chiba Y, Xu M, Mizoguchi I, Mizuguchi J, Yoshimoto T
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Presentation] Regulation of inflammatory immune responses leading to the development of bone destructive autoimmune disease rheumatoid arthritis by IL-27. Bio-Rhematology Internation Congress (BRIC) Tokyo (2011)
  • Author(s): Yoshimoto T, Xu M, Mizoguchi I, Chiba Y, Kamiya S, Matsui M, Shahrara S, Mizuguchi J
  • Organizer: The 8the GARN Meeting
  • Place of Presentation: Chiba, Japan
• [Presentation] Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production (2011)
  • Author(s): Xu M, Morishima N, Mizoguchi I, Chiba Y, Fujita K, Kuroda M, Iwakura Y, Cua DJ, Yasutomo K, Mizuguchi J, Yoshimoto T
  • Organizer: The 98th American Association of Immunologists Annual Meeting
  • Place of Presentation: San Francisco, California, USA
• [Presentation] Regulation of the development of acute hepatitis (2011)
  • Author(s): Xu, M. et al.
  • Organizer: 98th Annual Meeting of AAI
  • Place of Presentation: San Francisco, USA
• [Presentation] Regulation of the development of acute hepatitis (2011)
  • Author(s): Xu, M. et al.
  • Organizer: 第168回東京医科大学医学会総会
  • Place of Presentation: 東京
• [Presentation] IL-27 enhances poly(I:C)-induced apoptosis (2011)
  • Author(s): Chiba, Y. et al.
  • Organizer: 第40回日本免疫学会総会
  • Place of Presentation: 千葉
• [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 等
  • 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