Establishment of an IL-1-related gene-manipulated mice library, aiming at uncovering pathophysiology of disease from a view point of systems biology

2011 Fiscal Year Final Research Report

• Project/Area Number: 20220009
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Laboratory animal science
• Research Institution: The University of Tokyo
• Principal Investigator: IWAKURA Yoichiro 東京大学, 医科学研究所, 教授 (10089120)
• Co-Investigator(Kenkyū-buntansha): SAIJO Shinobu 千葉大学, 真菌医学研究センター, 特任准教授 (60396877) ; KAKUTA Shigeru 信州大学, 医学部, 助教 (80345032) ; FUJIKADO Noriyuki 東京大学, 医科学研究所, 助教 (90447334) ; KUSAKA Toshimasa 東京大学, 医科学研究所, 特任研究員 (60466836) ; KAIFU TomonoriI 東京大学, 医科学研究所, 助教 (90343037) ; CE Tang 東京大学, 医科学研究所, 助教 (00572166) ; MA GUANGYU 東京大学, 医科学研究所, 助教 (60572162)
• Project Period (FY): 2008 – 2011
• Keywords: サイトカイン / 疾患モデル動物 / 自己免疫疾患 / Th17細胞 / 関節リウマチ

Research Abstract

The project’s aim is to deeply understand the pathological and physiological roles of IL-1 and IL-1-relating genes in maintaining homeostasis and developing diseases in the immune, the nervous, and the endocrine system. In addition to evaluating the pathophysiological role of these genes, we intended to establish a system of bio-source to provide the gene-manipulated mice with all researchers. We newly generated five gene-targeting mice, which have been finished in backcrossing toward C57BL6/c background, and four additional gene-targeting mice (DCIR, IL-1R2, IL-1F6, and SCPL) were backcrossed to C57BL6/c background. We demonstrated that IL-1-related genes were involved in the regulation of bone metabolism and the development of autoimmune diseases, like arthritis. Moreover, IL-1 was a mediator in controlling activity of the nervous system and had a direct effect on lipid metabolism. On the basis of our analysis in gene-targeting mice, these mice are novel useful disease-models for analyzing the pathology of bony and autoimmune diseases. Finally, we set up the system that supplies gene-manipulated mice that we generated to all researchers, contributing to the progress of research horizons in laboratory animal.

Research Products

• [Journal Article] IL-1 signaling is dispensable for protective immunity in Leishmania-resistant mice (2011)
  • Author(s): Kautz-Neu, K., Kostka, S. L., Dinges, S., Iwakura, Y., Udey, M. C., and Von Stebut, E.
  • Journal Title: Exp. Dermatol. Volume: 20 Pages: 76-78
  • Peer Reviewed
• [Journal Article] Muramyldipeptide augments the actions of lipopolysacchairde in mice by stimulating macrophages to produe pro-IL-1B and by down-regulation of suppressor of cytokine signaling 1(SOCS1) (2011)
  • Author(s): Shikama, Y., Kuroishi, T., Nagai, Y., Iwakura, Y., Shimauchi, H., Takada, H., Sugawara, S., and Endo, Y.
  • Journal Title: Innate Immun. Volume: 17 Pages: 54-59
  • Peer Reviewed
• [Journal Article] Local microbleeding facilitates IL-6-and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells (2011)
  • Author(s): Murakami, M., Okuyama, Y., Ogura, H., Asano, S., Arima, Y., Tsuruoka, M., Harada, M., Kanamoto, M., Sawa, Y., Iwakura, Y., Takatsu, K., Kamimura, D., and Hirano, T.
  • Journal Title: J. Exp. Med. Volume: 208 Pages: 103-114
  • Peer Reviewed
• [Journal Article] G. Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation (2011)
  • Author(s): Rivera, A., Hohl, T. M., Collins, N., Leiner, I., Gallegos, A., Saijo, S., Coward, J. W., Iwakura, Y., and Pamer, E.
  • Journal Title: J. Exp. Med. Volume: 208 Pages: 369-381
  • Peer Reviewed
• [Journal Article] The role of glucocorticoids in pregnancy, parturition, lactation, and nurturing in melanocortin receptor 2. deficient mice (2011)
  • Author(s): Chida, D., Miyoshi, K., Sato, T., Yoda, T., Kikusui, T., and Iwakura, Y.
  • Journal Title: Endocrinology Volume: 152 Pages: 1652-1660
  • Peer Reviewed
• [Journal Article] Functional specialization of IL-17 family members (2011)
  • Author(s): Iwakura, Y., Ishigame, H., Saijo, S., and Nakae, S.
  • Journal Title: Immunity Volume: 34 Pages: 149-162
  • Peer Reviewed
• [Journal Article] Memory/effector(CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology (2011)
  • Author(s): Kamanaka, M., Huber, S., Zenewicz, L. A., Gagliani, N., Rathinam, C., O' Connor, W. Jr., Wan, Y. Y., Nakae, S., Iwakura, Y., Hao, L., and Flavell, R. A.
  • Journal Title: J. Exp. Med. Volume: 208 Pages: 1027-1040
  • Peer Reviewed
• [Journal Article] Dectin-1 and Dectin-2 in innate immunity against fungi (2011)
  • Author(s): Saijo, S., and Iwakura, Y.
  • Journal Title: Int. Immunol. Volume: 23 Pages: 467-472
  • Peer Reviewed
• [Journal Article] Control of T(H) 17 cells occurs in the small intestine (2011)
  • Author(s): Esplugues, E., Huber, S., Gagliani, N., Hauser, A. E., Town, T., Wan, Y. Y., O' Connor, W., Rongvaux, A., Van Rooijen, N., Haberman, A. M., Iwakura, Y., Kuchroo, V. K., Kolls, J. K., Bluestone, J. A., Herold, K. C., and Flavell, R. A.
  • Journal Title: Nature Volume: 475 Pages: 514-518
  • Peer Reviewed
• [Journal Article] Desmoglein 3-specific CD4+T cells induce pemphigus vulgaris and interface dermatitis in mice (2011)
  • Author(s): Takahashi, H., Kouno, M., Nagao, K., Wada, N., Hata, T., Nishimoto, S., Iwakura, Y., Yoshimura, A., Yamada, T., Kuwana, M., Fujii, H., Koyasu, S., and Amagai, M.
  • Journal Title: J. Clin. Invest. Volume: 121 Pages: 3677-3688
  • Peer Reviewed
• [Journal Article] Functional recovery after peripheral nerve injury is dependent on the proinflammatory cytokines IL-1. and TNF : implicaitons for neuropathic pain (2011)
  • Author(s): Nadeau, S., Filali, M., Zhang, J., Kerr, B. J., Rivest, S., Soulet, D., Iwakura, Y., de Rivero Vaccari, J. P., Keane, R. W., and Lacroix, S.
  • Journal Title: J. Neurosci. Volume: 31 Pages: 12533-12542
  • Peer Reviewed
• [Journal Article] IL-1 receptor accessory protein-like 1 associated with mental retardation and autism mediates synapse formation by trans-synaptic interaction with protein tyrosine phosphatase (2011)
  • Author(s): Yoshida, T., Yasumura, M., Uemura, T., Lee, S. J., Ra, M., Taguchi, R., Iwakura, Y., and Mishina, M.
  • Journal Title: J. Neurosci. Volume: 31 Pages: 13485-13499
  • Peer Reviewed
• [Journal Article] IFN-regulates the requirement for IL-17 in proteoglycan-induced arthritis (2010)
  • Author(s): Doodes, P. D., Cao, Y., Hamel, K. M., Wang, Y., Rodeghero, R. I., Mikecz, K., Glant T. T., Iwakura, Y., and Finnegan, A.
  • Journal Title: J. Immunol. Volume: 184 Pages: 1552-1559
  • Peer Reviewed
• [Journal Article] Neural tube defects and impaired neural progenitor cell proliferation in G. 1-deficient mice (2010)
  • Author(s): Okae, H., and Iwakura, Y.
  • Journal Title: Developmental Dynamics Volume: 239 Pages: 1089-1101
  • Peer Reviewed
• [Journal Article] Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung (2010)
  • Author(s): Okamoto Yoshida, Y., Umemura, M., Yahagi, A., O' Brien, R. L., Ikuta, K., Kishihara, K., Hara, H., Nakae, S., Iwakura, Y., and Matsuzaki, G.
  • Journal Title: J. Immunol. Volume: 184 Pages: 4414-4422
  • Peer Reviewed
• [Journal Article] Dectin-2 recognition ofα-mannans and induction of Th17 differentiation is essential for host defense against Candida albicans (2010)
  • Author(s): Saijo, S., Ikeda, S., Yamabe, K., Kakuta, S., Ishigame, H., Akitsu, A., Fujikado, N., Kusaka, T., Kubo, S., Chung, S., Komatsu, R., Miura, N., Adachi, Y., Ohno, N., Shibuya, K., Yamamoto, N., Kawakami, K., Yamasaki, S., Saito, T., Akira, S., and Iwakura,
  • Journal Title: Immunity Volume: 32 Pages: 681-691
  • Peer Reviewed
• [Journal Article] IL-17 is necessary for host protection against acute-phase Trypanosoma cruzi infection (2010)
  • Author(s): Miyazaki, Y., Hamano, S., Wang, S., Shimanoe, Y., Iwakura, Y., and Yoshida, H.
  • Journal Title: J. Immunol. Volume: 185 Pages: 1150-1157
  • Peer Reviewed
• [Journal Article] M. Type I interferon signaling constrains IL-17A/F secretion byγδT cells during bacterial infection (2010)
  • Author(s): Henry, T., Kirimanjeswara, G. S., Ruby, T., Jones, J. W., Peng, K., Perret, M., Ho, L., Sauer, J.-D., Iwakura, Y., Metzger, D. W., and Monack, D.
  • Journal Title: J. Immunol. Volume: 184 Pages: 3755-3767
  • Peer Reviewed
• [Journal Article] TNF, but not IL-6 and IL-17, is crucial for the development of T cell-independent psoriasis-like dermatitis in Il1rn^<-/-> mice (2010)
  • Author(s): Nakajima, A., Matsuki, T., Komine, M., Asahina, A., Horai, R., Nakae, S., Ishigame, H., Kakuta, S., Saijo, S., and Iwakura, Y.
  • Journal Title: J. Immunol. Volume: 185 Pages: 1887-1893
  • Peer Reviewed
• [Journal Article] IL-1 plays an important role in the bone metabolism under physiological conditions (2010)
  • Author(s): Lee, Y.-M., Fujikado, N., Manaka, H., Yasuda, H., and Iwakura, Y.
  • Journal Title: Int. Immunol. Volume: 22 Pages: 805-816
  • Peer Reviewed
• [Journal Article] D. Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis (2010)
  • Author(s): Chou, R. C., Kim, N. D., Sadik, C. D., Seung, E., Lan, Y., Byrne, M. H., Haribabu, B., Iwakura, Y., and Luster, A.
  • Journal Title: Immunity Volume: 33 Pages: 266-278
  • Peer Reviewed
• [Journal Article] L. Lung CD4-CD8-double-negative T cells are prominent producers of IL-17A and IFN-during primary respiratory murine infection with Francisella tularensis live vaccine strain (2010)
  • Author(s): Cowley, S. C., Meierovics, A. I., Frelinger, J. A., Iwakura, Y., and Elkins, K.
  • Journal Title: J. Immunol. Volume: 184 Pages: 5791-5801
  • Peer Reviewed
• [Journal Article] CXC chemokine receptor 4 expressed in T cells plays an important role in the development of collagen-induced arthritis (2010)
  • Author(s): Chung, S. H., Seki, K., Choi, B. I., Kimura, K. B., Ito, A., Fujikado, N., Saijo, S., and Iwakura, Y.
  • Journal Title: Arthritis Res. Ther. Volume: 12 Pages: 188
  • Peer Reviewed
• [Journal Article] Differential roles of IL-17A and IL-17F in host defense against mucoepithelial bacterial infection and allergic responses (2009)
  • Author(s): Ishigame, H., Kakuta, S., Nagai, T., Nambu, A., Komiyama, Y., Kadoki, M., Tanahashi, Y., Akitsu, A., Kotaki, H., Sudo, K., Nakae, S., Sasakawa, C., and Iwakura, Y
  • Journal Title: Immunity Volume: 30 Pages: 108-119
  • Peer Reviewed
• [Journal Article] IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice (2009)
  • Author(s): Lopez Kostka, S., Dinges, S., Griewank, K., Iwakura, Y., Udey, M. C., and Von Stebut, E.
  • Journal Title: J. Immunol. Volume: 182 Pages: 3039-3046
  • Peer Reviewed
• [Journal Article] M. Virus binding to a plasma membrane receptor triggers interleukin-1α-mediated proinflammatory macrophage response in vivo (2009)
  • Author(s): Di Paolo, N. C., Miao, E. A., Iwakura, Y., Kaja, M-K., Aderem, A., Flavell, R. A., Papayannopoulou, T., and Shayakhmetov, D.
  • Journal Title: Immunity Volume: 31 Pages: 110-121
  • Peer Reviewed
• [Journal Article] Characterization of mice deficient in Melanocortin 2 receptor on a B6/Balbc mix background (2009)
  • Author(s): Chida, D., Sato, T., Sato, Y., Kubo, M., Yoda, T., Suzuki, H., and Iwakura, Y.
  • Journal Title: Mol. Cell. Endocrinol. Volume: 300 Pages: 32-36
  • Peer Reviewed
• [Journal Article] Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation (2009)
  • Author(s): Inoue, A., Setoguchi, K., Matsubara, Y., Okada, K., Sato, N., Iwakura, Y., Higuchi, O., and Yamanashi, Y.
  • Journal Title: Science Signaling Volume: 2 Pages: 7
  • Peer Reviewed
• [Journal Article] A. A protective function for interleukin 17A in T cell-mediated intestinal inflammation (2009)
  • Author(s): O' Connor, W. Jr., Kamanaka, M., Booth, C. J., Town, T., Nakae, S., Iwakura, Y., Kolls, J. K., and Flavell, R.
  • Journal Title: Nat. Immunol. Volume: 10 Pages: 603-609
  • Peer Reviewed
• [Journal Article] E. Pulmonary inflammation triggered by Ricin toxin requires macrophages and IL-1 signaling (2009)
  • Author(s): Lindauer, M. L., Wong, J., Iwakura, Y., and Magun, B.
  • Journal Title: J. Immunol. Volume: 183 Pages: 1419-1426
  • Peer Reviewed
• [Journal Article] Pivotal role of cerebral interleukin-17-producingγδT cells in the delayed phase of ischemic brain injury (2009)
  • Author(s): Shichita, T., Sugiyama, Y., Ooboshi, H., Sugimori, H., Nakagawa, R., Takada, I., Iwaki, T., Okada, Y., Iida, M., Cua, D. J., Iwakura, Y., and Yoshimura, A.
  • Journal Title: Nat. Med. Volume: 15 Pages: 946-950
  • Peer Reviewed
• [Journal Article] Interleukin(IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17 (2009)
  • Author(s): Munoz, M., Heimesaat, M. M., Danker, K., Struck, D., Lohmann, U., Plickert, R., Bereswill, S., Fischer, A., Dunay, I. R., Wolk, K., Loddenkemper, C., Krell, H.-W., Libert, C., Lund, L. R., Frey, O., Holscher, C., Iwakura, Y., Ghilardi, N., Ouyang, W., Kamradt, T., Sabat, R., and Liesenfeld, O.
  • Journal Title: J. Exp. Med. Volume: 206 Pages: 3047-3059
  • Peer Reviewed
• [Journal Article] Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of Natural Killer T cells and IL-17 (2008)
  • Author(s): Pichavant, M., Goya, S., Meyer, E. H., Johnston, R. A., Kim, H. Y., Matangkasombut, P., Zhu, M., Iwakura, Y., Savage, P. B., DeKruyff, R. H., Shore, S. A., and Umetsu, D. T.
  • Journal Title: J. Exp. Med. Volume: 205 Pages: 385-393
  • Peer Reviewed
• [Journal Article] The roles of IL-17A in inflammatory immune responses and host defense against pathogens (2008)
  • Author(s): Iwakura, Y., Nakae, S., Saijo, S., and Ishigame, H.
  • Journal Title: Immunological Rev. Volume: 226 Pages: 57-79
  • Peer Reviewed
• [Journal Article] K. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia (2008)
  • Author(s): Aujla, S. J., Fei, M., Pociask, D. A., Reinhart, T. A., Edeal, J., Gaus, K., Kreindler, J. L., Dubin, P. J., Zheng, M., Pilewski, J. M., Myerburg, M. M., Mason, C. A., Iwakura, Y., and Kolls, J.
  • Journal Title: Nature Med. Volume: 14 Pages: 275-281
  • Peer Reviewed
• [Journal Article] Either a Th17 or a Th1 effector response can drive autoimmunity : conditions of disease induction affect dominant effector category (2008)
  • Author(s): Luger, D., Silver, P. B., Tang, J., Cua, D., Chen, Z., Iwakura, Y., Bowman, E. P., Sgambellone, N. M., Chan, C.-C. and Caspi, R.
  • Journal Title: J. Exp. Med. Volume: 205 Pages: 799-810
  • Peer Reviewed
• [Journal Article] Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis (2008)
  • Author(s): Izcue, A., Hue, S., Buonocore, S., Arancibia-Carcamo, C. V., Ahern, P. P., Iwakura, Y., Maloy, K. J., and Powrie, F
  • Journal Title: Immunity Volume: 28 Pages: 559-570
  • Peer Reviewed
• [Journal Article] L-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8^+T cells (2008)
  • Author(s): Tajima, M., Wakita, D., Noguchi, D., Chamoto, K., Yue, Z, Fugo, K., Ishigame, H., Iwakura, Y., Kitamura, H., and Nishimura, T
  • Journal Title: J. Exp. Med. Volume: 205 Pages: 1019-1027
  • Peer Reviewed
• [Journal Article] Increased fat-to-carbohydrate oxidation ratio in Il1ra^<-/-> mice on a high fat diet is associated with increased sympathetic tone (2008)
  • Author(s): Chida, D., Hashimoto, O., Kuwahara, M., Sagara, H., Osaka, T., Tsubone, H., and Iwakura, Y.
  • Journal Title: Diabetologia Volume: 51 Pages: 1698-1706
  • Peer Reviewed
• [Journal Article] Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction (2008)
  • Author(s): Ogura, H., Murakami, M., Okyuyama, Y., Tsuruoka, M., Kitabayashi, C., Kanamoto, M., Nishihara, M., Iwakura, Y., and Hirano, T.
  • Journal Title: Immunity Volume: 29 Pages: 628-636
  • Peer Reviewed
• [Journal Article] The role of DCIR in the development of autoimmune diseases (2008)
  • Author(s): Fujikado, N., Saijo, S., Yonezawa, T., Shimamori, K., Ishii, A., Sugai, S., Kotaki, H., Sudo, K., Nose, M., and Iwakura, Y.
  • Journal Title: Cytokine Volume: 43 Pages: 244
  • Peer Reviewed
• [Journal Article] The mechanisms of the stress-induced behavioral abnormality in the IL-1 receptor antagonist(IL-1Ra) KO mice (2008)
  • Author(s): Wakabayashi, C., and Iwakura, Y.
  • Journal Title: Neuroscience Res. Volume: 61 Pages: 63
  • Peer Reviewed
• [Journal Article] Contribution of IL-1 to resistance to Streptococcus pneumoniae infection (2008)
  • Author(s): Kafka, D., Ling, E., Feldman, G., Benharroch, D., Voronov, E., Givon-Laci, N., Iwakura, Y., Dagan, R., Apte, R. N., and Mizrachi-Nebenzahi, Y.
  • Journal Title: Int. Immunol. Volume: 9 Pages: 1139-1146
  • Peer Reviewed
• [Presentation] Therapeutic targets for rheumatoid arthritis : lessons from animal models (2011)
  • Author(s): Yoichiro Iwakura
  • Organizer: Bio-Rheumatology International Congress(BRIC) Tokyo、The 8th GARN Meeting
  • Place of Presentation: Hilton Tokyo Bay Hotel
  • Year and Date: 20111114-16
• [Presentation] Gene manipulated mice as a tool for the analysis of pathogenesis and development of new therapeutics (2011)
  • Author(s): Yoichiro Iwakura
  • Organizer: Animal Research Center
  • Place of Presentation: Jirin University, Changchun
  • Year and Date: 20111114-16
• [Presentation] The roles of IL-17A and IL-17F in the immune system (2009)
  • Author(s): Yoichiro Iwakura
  • Organizer: Th17 Cells in Health and Disease, Keystone Symposium
  • Place of Presentation: British Columbia, Canada
  • Year and Date: 20090205-10
• [Presentation] The role of DCIR in the development of autoimmune arthritis (2008)
  • Author(s): Yoichiro Iwakura
  • Organizer: The Australian Health and Medical Research Congress, Brisbane Convention Center
  • Place of Presentation: Brisbane, Australia
  • Year and Date: 20081116-21
• [Book] 免疫疾患.疾患モデルの作製と利用.シリーズ「モデル動物利用マニュアル」 (2011)
  • Author(s): 岩倉洋一郎
  • Total Pages: 580
  • Publisher: エル・アイ・シー
• [Book] アグリゲーション法によるキメラマウスの作製.改訂第5版新遺伝子工学ハンドブック (2010)
  • Author(s): 角田茂、佐藤希、久保幸子、岩倉洋一郎
  • Total Pages: 289-296
  • Publisher: 羊土社
• [Book] Dcirと自己免疫疾患最新医学 (2009)
  • Author(s): 藤門範行、岩倉洋一郎
  • Total Pages: 913-918
• [Book] サイトカインシグナルと代謝疾患 (2008)
  • Author(s): 千田大、岩倉洋一郎
  • Total Pages: 476-479
  • Publisher: ニュー・サイエンス社
• [Remarks]
  • URL: http://www.rs.tus.ac.jp/iwakuralab/
• [Patent(Industrial Property Rights)] 骨免疫疾患の予防・治療剤 (2010)
  • Inventor(s): 岩倉洋一郎、藤門範行、馬光宇
  • Industrial Property Rights Holder: 国立大学法人,東京大学, 他3名
  • Industrial Property Number: 2010-37204
  • Filing Date: 2010-02-23
• [Patent(Industrial Property Rights)] IL-1タイプIIレセプター遺伝子の欠損変異体マウス (2009)
  • Inventor(s): 岩倉洋一郎、角田茂, 他4名
  • Industrial Property Rights Holder: 国立大学法人,東京大学, 他10名
  • Industrial Property Number: 公開特許公報(A)、2009-183176
  • Acquisition Date: 2009-08-20