Identification of target protein(s) to abrogate chronic inflammation

• Project/Area Number: 23659404
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Juntendo University
• Principal Investigator: NAKANO Hiroyasu 順天堂大学, 医学部, 准教授 (70276476)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: TRAF2 / 腸炎 / インターロイキン 10 / TNFa / 好中球 / 炎症性腸炎 / インターロイキン10 / LPS / MDSC

Research Abstract

IL-10-secreting neutrophils accumulated in peripheral blood and bone marrow (BM) cells from Traf2-/- mice compared to wild-type mice. Treatment of Traf2-/- mice with neutralizing antibody against TNFa or crossing Traf2-/- mice with Tnfr1-/- mice reduced the percentages of IL-10-secreting neutrophils, suggesting that the development of IL-10-secreting neutrophils largely depended on TNFa signal. Finally, combined treatment of Traf2-/- mice with neutralizing antibodies against TNFa and IL-10, but not each antibody alone, substantially ameliorated colitis and prolonged survival. Together, abrogation of immunosuppressive conditions mediated by IL-10-secreting neutrophils might be an alternative strategy to treat chronic inflammatory diseases.

Research Products

• [Journal Article] Tumor Necrosis Factor Receptor Associated Factor 5 is an Essential Mediator of Ischemic Brain Infarction (2013)
  • Author(s): Wang, L., Y. Lu, H. Guan, D. Jiang, Y. Guan, X. Zhang, H. Nakano, Y. Zhou, Y. Zhang, L. Yang, and H. Li
  • Journal Title: J Neurochem
  • Peer Reviewed
• [Journal Article] Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation (2013)
  • Author(s): Shindo, R., H. Kakehashi, K. Okumura, Y. Kumagai, and H. Nakano
  • Journal Title: Biochem Biophys Res Commun
  • Peer Reviewed
• [Journal Article] Hyperosmotic stress regulates the distribution and stability of myocardin-related transcription factor, a key modulator of the cytoskeleton (2013)
  • Author(s): Ly, D.L., F. Waheed, M. Lodyga, P. Speight, A. Masszi, H. Nakano, M. Hersom, S.F. Pedersen, K. Szaszi, and A. Kapus
  • Journal Title: Am J Physiol Cell Physiol Volume: 304
  • Peer Reviewed
• [Journal Article] Shigella IpaH0722 E3 ubiquitin ligase effector targets TRAF2 to inhibit PKC-NF-kB activity in invaded epithelial cells (2013)
  • Author(s): Ashida, H., H. Nakano, and C. Sasakawa
  • Journal Title: PLoS Pathogens
  • Peer Reviewed
• [Journal Article] c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. (2013)
  • Author(s): Piao X
  • Journal Title: Sci Signal Volume: ra93 Issue: 255
  • DOI: 10.1126/scisignal.2003558
  • Peer Reviewed
• [Journal Article] Tumor Necrosis Factor Receptor Associated Factor 5 is an Essential Mediator of Ischemic Brain Infarction (2013)
  • Author(s): Lang Wang et al
  • Journal Title: J Neurochem Volume: in press Issue: 3 Pages: 400-414
  • DOI: 10.1111/jnc.12207
  • Peer Reviewed
• [Journal Article] c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis (2012)
  • Author(s): Piao, X., S. Komazawa-Sakon, T. Nishina, M. Koike, J.H. Piao, H. Ehlken, H. Kurihara, M. Hara, N. Van Rooijen, G. Schutz, M. Ohmuraya, Y. Uchiyama, H. Yagita, K. Okumura, Y.W. He, and *H. Nakano
  • Journal Title: Sci Signal Volume: 5 Pages: 93-93
  • Peer Reviewed
• [Journal Article] Aberrant accumulation of interleukin-10-secreting neutrophils in TRAF2-deficient mice (2012)
  • Author(s): Piao, J.H., H. Yagita, K. Okumura, and *H. Nakano
  • Journal Title: Immunol Cell Biol Volume: 90 Pages: 881-888
  • Peer Reviewed
• [Journal Article] Interleukin-11 links oxidative stress and compensatory proliferation (2012)
  • Author(s): Nishina, T., S. Komazawa-Sakon, S. Yanaka, X. Piao, D.M. Zheng, J.H. Piao, Y. Kojima, S. Yamashina, E. Sano, T. Putoczki, T. DOI:, T. Ueno, J. Ezaki, H. Ushio, M. Ernst, K. Tsumoto, K. Okumura, and *H. Nakano
  • Journal Title: Sci Signal Volume: 5 Pages: 5-5
  • NAID: 130006999375
  • Peer Reviewed
• [Journal Article] Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice (2012)
  • Author(s): Minami, T., K. Kuwahara, Y. Nakagawa, M. Takaoka, H. Kinoshita, K. Nakao, Y. Kuwabara, Y. Y amada, C. Yamada, J. Shibata, S. Usami, S. Yasuno, T. Nishikimi, K. Ueshima, M. Sata, H. Nakano, T. Seno, Y. Kawahito, K. Sobue, A. Kimura, R. Nagai, and K. Nakao.
  • Journal Title: EMBO J Volume: 31 Pages: 4428-4440
  • Peer Reviewed
• [Journal Article] Interleukin-11 Links Oxidative Stress and Compensatory Proliferation (2012)
  • Author(s): Nishina T, Komazawa-Sakon S, Yanaka S, Zheng X, Palo J, Kojima Y, Yamashina S, Sano E, Putoczki T, Doi T, Ueno T, Ezaki J, Ushio H, Ernst M, Kouhei T, Okamura K, Nakano H
  • Journal Title: Science Signal Volume: 5 Issue: 207
  • DOI: 10.1126/scisignal.2002056
  • Peer Reviewed
• [Journal Article] Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodeling in mice. (2012)
  • Author(s): Minami T, Nakao K, et al
  • Journal Title: EMBO J. Volume: 31 Issue: 23 Pages: 4428-4440
  • DOI: 10.1038/emboj.2012.296
  • Peer Reviewed
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (2012)
  • Author(s): Daniel J Klionsky et al
  • Journal Title: Autophagy Volume: 8 Pages: 445-554
  • Peer Reviewed
• [Journal Article] Hyperosmotic stress regulates the distribution and stability of myocardin-related transcription factor, a key modulator of the cytoskeleton (2012)
  • Author(s): Donald L Ly et al
  • Journal Title: Am J Physiol Cell Physiol Volume: 304 Issue: 2 Pages: C115-C127
  • DOI: 10.1152/ajpcell.00290.2012
  • Peer Reviewed
• [Journal Article] Crucial role for autophagy in degranulation of mast cells (2011)
  • Author(s): Ushio, H., T. Ueno, Y. Kojima, M. Komatsu, S. Tanaka, A. Yamamoto, Y. Ichimura, J. Ezaki, K. Nishida, S. Komazawa-Sakon, F. Niyonsaba, T. Ishii, T. Yanagawa, E. Kominami, H. Ogawa, K. Okumura, and *H. Nakano
  • Journal Title: J Allergy Clin Immunol Volume: 127
  • Peer Reviewed
• [Journal Article] SHARPIN is a component of the NF-kB-activating linear ubiquitin chain assembly complex (2011)
  • Author(s): Tokunaga, F., T. Nakagawa, M. Nakahara, Y. Saeki, M. Taniguchi, S. Sakata, K. Tanaka, H. Nakano, and K. Iwai
  • Journal Title: Nature Volume: 471 Pages: 633-636
  • Peer Reviewed
• [Journal Article] Tumor Necrosis Factor Receptor-associated Factor (TRAF) 2 Controls Homeostasis of the Colon to Prevent Spontaneous Development of Murine Inflammatory Bowel Disease (2011)
  • Author(s): Piao, J.H., M. Hasegawa, B. Heissig, K. Hattori, K. Takeda, Y. Iwakura, K. Okumura, N. Inohara, and *H. Nakano
  • Journal Title: J Biol Chem Volume: 286 Pages: 17879-17888
  • Peer Reviewed
• [Journal Article] An unexpected role for autophagy in degranulation of mast cells (2011)
  • Author(s): *Nakano, H., and H. Ushio
  • Journal Title: Autophagy Volume: 7 Pages: 657-659
  • Peer Reviewed
• [Journal Article] Importin beta1 Protein-mediated Nuclear Localization of Death Receptor 5 (DR5) Limits DR5/Tumor Necrosis Factor(TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Cell Death of Human Tumor Cells (2011)
  • Author(s): Kojima, Y., M. Nakayama, T. Nishina, H. Nakano, M. Koyanagi, K. Takeda, K. Okumura, and H. Yagita
  • Journal Title: J Biol Chem Volume: 286 Pages: 43383-43393
  • Peer Reviewed
• [Journal Article] beta-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition (2011)
  • Author(s): Charbonney, E., P. Speight, A. Masszi, H. Nakano, and A. Kapus
  • Journal Title: Mol Biol Cell Volume: 22 Pages: 4472-4485
  • Peer Reviewed
• [Journal Article] Sharpin is a component of the NF-κB activating linear ubiquitin chain assembly complex (2011)
  • Author(s): Tokunaga, F., Nakagawa, T., Nakahara, M., Saeki, Y., Taniguchi, M., Sakata, S., Tanaka, K., Nakano, H., Iwai, I.
  • Journal Title: Nature Volume: 471 Issue: 7340 Pages: 633-636
  • DOI: 10.1038/nature09815
  • Peer Reviewed
• [Journal Article] Crucial role for autophagy in degranulation of mast cells (2011)
  • Author(s): Ushio, et al
  • Journal Title: J Allergy Clin Immunol Volume: 127 Issue: 5 Pages: 1267-1276
  • DOI: 10.1016/j.jaci.2010.12.1078
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor receptor-associated factor (TRAF) 2 control homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease (2011)
  • Author(s): Piao, J.H., Hasegawa, M., et al
  • Journal Title: J.Biol.Chem. Volume: 286 Issue: 20 Pages: 17879-17888
  • DOI: 10.1074/jbc.m111.221853
  • Peer Reviewed
• [Journal Article] Importin β1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells (2011)
  • Author(s): Kojima Y, Nakayama M, Nishina T, Nakano H, Koyanagi M, Takeda K, Okumura K, Yagita H
  • Journal Title: J Biol Chem Volume: 286 Issue: 50 Pages: 43383-43393
  • DOI: 10.1074/jbc.m111.309377
  • Peer Reviewed
• [Journal Article] beta-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition (2011)
  • Author(s): Charbonney, et al
  • Journal Title: Mol Biol Cell Volume: 22 Issue: 23 Pages: 4472-4485
  • DOI: 10.1091/mbc.e11-04-0335
  • Peer Reviewed
• [Presentation] 酸化ストレスにより誘導されるIL-11が肝細胞の代償性増殖を誘導する (2012)
  • Author(s): 中野 裕康 他
  • Organizer: 第19回肝細胞研究会・シンポジウム
  • Place of Presentation: 札幌医科大学臨床教育研究棟、札幌
• [Presentation] 酸化ストレスと組織修復を仲介する分子の同定 (2012)
  • Author(s): 仁科 隆史 他
  • Organizer: 第19回肝細胞研究会・シンポジウム
  • Place of Presentation: 札幌医科大学臨床教育研究棟、札幌
• [Presentation] c-FLIP maintains tissue homeostasis by preventing apoptosis and necroptosis (2012)
  • Author(s): 中野 裕康
  • Organizer: 第35回日本分子生物学会年会・ワークショップ
  • Place of Presentation: 福岡マリンメッセ
  • Invited
• [Presentation] 親電子分子によるIL-11産生機構の解明 (2012)
  • Author(s): 仁科 隆史 他
  • Organizer: 第35回日本分子生物学会年会・ワークショップ
  • Place of Presentation: 福岡マリンメッセ
• [Presentation] c-FLIP maintains tissue homeostasis by preventing apoptosis and necroptosis (2012)
  • Author(s): 朴 雪花 他
  • Organizer: 第41回日本免疫学総会
  • Place of Presentation: 神戸交際会議場
• [Presentation] Interleukin 11 links Oxidative Stress and Compensatory Proliferation (2012)
  • Author(s): Hiroyasu Nakano
  • Organizer: The 33rd NAITO Conference on Oxygen Biology: Hypoxia, Oxidative Stress and Diseases
  • Place of Presentation: Sapporo, Japan
• [Presentation] An essential Role for c-FLIP in maintaining homeostasis of the intestine and the liver by preventing apoptosis and programmed necrosis (2012)
  • Author(s): Xuehua Piao et al
  • Organizer: The 12th Biennial International Endotoxin & Innate Immunity Society (IEIIS) meeting
  • Place of Presentation: Tokyo, Japan
• [Presentation] Interleukin 11 links Oxidative Stress and Compensatory Proliferation (2012)
  • Author(s): Takashi Nishina et al
  • Organizer: he 12th Biennial International Endotoxin & Innate Immunity Society (IEIIS) meeting
  • Place of Presentation: Tokyo, Japan
• [Presentation] Oxidative stress maintains tissue homeostasis by inducing compensatory proliferation (2012)
  • Author(s): Hiroyasu Nakano
  • Organizer: International Symposium 2012 on Signaling Functions of Reactive Oxygen Species
  • Place of Presentation: Fukuoka, Japan
  • Invited
• [Presentation] Interleukin 11 links Oxidative Stress and Compensatory Proliferation (2012)
  • Author(s): Nishina et al
  • Organizer: Symposium on Biological Complexity: Immunity and Inflammation
  • Place of Presentation: Salk Institute, San Diego, USA
• [Presentation] An Indispensable Role for c-FLIP in Postnatal Survival of Hepatocytes by Preventing Apoptosis and Necrosis (2012)
  • Author(s): Nakano et al
  • Organizer: Symposium on Biological Complexity: Immunity and Inflammation
  • Place of Presentation: Salk Institute, San Diego, USA
• [Presentation] 酸化ストレスと組織修復を連結する因子の同定 (2011)
  • Author(s): 中野裕康
  • Organizer: 第20回日本Cell Death学会学術集会(招待講演)
  • Place of Presentation: 東京大学薬学総合研究棟講堂（東京都）
• [Presentation] 酸化ストレスと組織修復を連結する因子の同定 (2011)
  • Author(s): 中野裕康
  • Organizer: 第54回日本放射線影響学会(招待講演)
  • Place of Presentation: 神戸商工会議所会館（神戸市）
• [Presentation] Interleukin 11 links oxidative stress and compensatory proliferation (2011)
  • Author(s): 中野裕康
  • Organizer: 第40回日本免疫学会総会(招待講演)
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Interleukin 11 links oxidative stress and compensatory proliferation (2011)
  • Author(s): Nishina et al
  • Organizer: 13th International TNF Conference
  • Place of Presentation: 淡路夢舞台国際会議場 （兵庫県）
• [Presentation] TRAF2 controls homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease (2011)
  • Author(s): Piao et al
  • Organizer: 13th International TNF Conference
  • Place of Presentation: 淡路夢舞台国際会議場 （兵庫県）
• [Presentation] 酸化ストレスにより誘導されるIL-11は代償性増殖に関与する (2011)
  • Author(s): 仁科 隆史 他
  • Organizer: 第20回日本Cell Death学会学術集会
  • Place of Presentation: 東京大学薬学総合研究棟講堂（東京都）
• [Presentation] TRAF2 controls homeostasis of the colon to prevent spontaneous development of inflammatory bowel disease (2011)
  • Author(s): 朴 将虎 他
  • Organizer: 第20回日本Cell Death学会学術集会
  • Place of Presentation: 東京大学薬学総合研究棟講堂（東京都）
• [Presentation] An essential role for cellular FLICE inhibitory protein in the postnatal development and protection of hepatocytes from Necrosis and apoptosis (2011)
  • Author(s): Xuehua Piao et al
  • Organizer: 第40回日本免疫学会総会
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Aberrant accumulation of IL-10-producing Gr1+CD11b+ neutrophils in traf2-/- mice (2011)
  • Author(s): Jiang-Hu Piao et al
  • Organizer: 第40回日本免疫学会総会
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Interleukin 11 links oxidative stress and compensatory proliferation (2011)
  • Author(s): 仁科 隆史 他
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Remarks] ホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/meneki/home.html
• [Remarks] 順天堂大学免疫学
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/meneki/home.html