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Laboratory for Cytokine Signaling
Toshio HIRANO
Group Director
Toshio HIRANO (M.D., Ph.D.)
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Research Areas

Despite their increasing prevalence in developed countries, the molecular mechanisms leading to autoimmune diseases and allergies remain poorly understood. The eventual goal of the Cytokine Signaling Research Group is to help elucidate the underlying molecular and immunological mechanisms of autoim-mune diseases and allergy from the viewpoint of signal transduction within the immune system. Recently, we have reported that heavy metal cations such as Zinc (Zn) might act as intracellular signaling molecules, i.e., molecules whose intracellular status is altered in response to an extracellular stimulus, and that are capable of transducing the extracellular stimulus into an intracellular signaling event. Zn is known to be important in the immune system, although its precise roles and mechanisms have not been resolved. Therefore, we are focusing our attention on the largely unknown universe of signaling through Zn transporter proteins, to reveal the role of Zn in immune and other physiological systems.

Research Subject

  1. Molecular mechanism of mast cell-mediated allergic reaction
  2. Roles of cytokine and zinc signaling in immune system and connective tissues

Related links

  1. RIKEN Research Center for Allergy and Immunology Website_Laboratories PageNew Window
  2. Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University New Window

Press release

May 18, 2009
Zinc transporter is found to play a role in allergy-type contact dermatitis, a discovery that will spur progress in developing effective treatments for dermatitis caused by contact with, for example, perfume, metal, and house dust.
May 14, 2007
Laboratory for Cytokine Signaling of RCAI in collaboration with Osaka University discovered that zinc has a role as a secondary intracellular messenger.

RIKEN RESEARCH

October 24, 2007
Identification of a novel cellular messenger
Zinc acts as second messenger in the cell to propagate extracellular signalsNew Window
September 08, 2006
Uncovering a secret messenger
Scientists reveal first evidence that zinc plays an active role in immune response and, possibly, cellular signalingNew Window

List of Selected Publications

  1. Hojyo S., T. Fukada, S. Shimoda, W. Ohashi, BH. Bin, H. Koseki, T. Hirano.:
    "The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth."
    PLoS ONE in press. (2011)
  2. Murakami, M., Y. Okuyama, H. Ogura, S. Asano, Y. Arima, M. Tsuruoka, M. Harada, M. Kanamoto, Y. Sawa, Y. Iwakura, K. Takatsu, D. Kamimura, T. Hirano.:
    "Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells."
    J. Exp. Med. 208, 103-114, (2011)
  3. Kitabayashi C., T. Fukada, M. Kanamoto1, W. Ohashi, S. Hojyo, T. Atsumi, N. Ueda, I. Azuma, H. Hirota, M. Murakami, and T. Hirano.:
    "Zinc suppresses Th17 development via inhibition of STAT3 activation."
    Int. Immunol. 22, 375-386, (2010)
  4. Hirano, T., M. Murakami, T. Fukada, K. Nishida, S. Yamasaki, and T. Suzuki.:
    "Roles of Zinc and Zinc signaling in immunity: Zinc is an intracellular signaling molecule."
    Advances in Immunology. 97, 149-176, (2008)
  5. Nishida K., A. Hasegawa, S. Nakae, K. Oboki, H. Saito, S. Yamasaki, and T. Hirano.:
    "Zinc transporter Znt5/Slc30a5 is required for the mast cell-mediated delayed-type allergic reaction but not the immediate-type reaction."
    J. Exp. Med. 206, 1351-1364, (2009)
  6. Sawa Y., Y. Arima, H. Ogura, C. Kitabayashi, J-J Jiang, T. Fukushima, D. Kamimura, T. Hirano, and M. Murakami.:
    "Hepatic Interleukin-7 Expression Regulates T Cell Responses."
    Immunity 30, 447-457, (2009)
  7. Fukada, T., N. Civic, T. Furuichi, S. Shimoda, K. Mishima, H. Higashiyama, Y. Idaira, Y. Asada, H. Kitamura, S. Yamasaki, S. Hojyo, M. Nakayama, O. Ohara, H. Koseki, H.G. dos Santos, L. Bonafe, R. Ha-Vinh, A. Zankl, S. Unger, M.E. Kraenzlin, J.S. Beckmann, I. Saito, C. Rivolta, S. Ikegawa, A. Superti-Furga, and T. Hirano.:
    "The Zinc Transporter SLC39A13/ZIP13 is Required for Connective Tissue Development; Its Involvement in BMP/TGF-β Signaling Pathways."
    PLoS ONE 3 (11), e3642, (2008)
  8. Ogura, H., M. Murakami, Y. Okuyama, M. Tsuruoka, C. Kitabayashi, M. Kanamoto, M. Nishihara, Y. Iwakura and T. Hirano.:
    "Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction."
    Immunity. 29, 628-636, (2008)
  9. Nishihara, M., H. Ogura, N. Ueda, M. Tsuruoka, C. Kitabayashi, F. Tuji, H. Aono, K. Ishihara, E. Huseby, U. A.K.Betz, M. Murakami and T. Hirano.:
    "IL-6-gp130-STAT3 in T cells directs the development of IL-17+T helper cells with a minimum effect on that of Treg in the steady state."
    Int. Immunol. 19, 695-702 (2007)
  10. Yamasaki, S., K. Sakata-Sogawa, A. Hasegawa, T. Suzuki, K. Kabu, E. Sato, T. Kurosaki, S. Yamashita, M. Tokunaga, K. Nishida and T. Hirano.:
    "Zinc is a novel intracellular second messenger."
    J. Cell Biol. 177, 637-645 (2007)
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