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Laboratory for Cytokine Signaling 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. Group director Toshio Hirano Senior Research Scientists : Toshiyuki Fukada Keigo Nishida Research Scientists Technical Staff Student Trainees : Satoru Yamasaki Tomoyuki Suzuki (SPR) : Ayumi Ito Yuko Ishikura Masami Kawamura Satoko Ojimi Yoshiki Sugibayashi Mayumi Hara : Shintaro Hojyo (JRA) Aiko Hasegawa The Role of Zn transporters in immune function. In a breakthrough discovery, we identified the zinc transporter Zip6 as a target gene of the IL-6 cytokine signaling molecule STAT3 and further demonstrated that Zip6 plays an important role in cell migration during gastrulation in the zebrafish (Yamashita et al, Nature, 2004). We showed that Zip6 is required for nuclear localization of Zn-finger protein Snail, a repressor of E-cadherin. This result led to the prediction that Zn might act as a signaling molecule like Ca2 + . Zn is a trace element that is essential for the function of many enzymes and transcription factors and thereby Zn is one of the important constitutive components of our body. However, little is known concerning its role as a signaling molecule. Zn deficiency results in defects in innate and acquired immune responses, but little is known how zinc controls immune cell function. In 2006, we found that the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) altered the intracellular level of free Zn by changing the expression profile of Zn transporters in dendritic cells (DC). This LPSinduced decrease of intracellular free Zn is one of critical steps for DC maturation; upregulation of surface MHCII and costimulatory molecules required for CD4 + T cell responses (Kitamura et al, Nature Immunology, 2006). Taken together Assistants : Ryoko Masuda Mizuki Shimura 66
with the aforementioned fact that FcεR stimulation induces a Zn wave in mast cells, our results showed that Zn is a novel intracellular signaling molecule like Ca 2+ and that Zn plays crucial roles in immune and allergy responses. To further clarify the in vivo roles Zn, we are currently establishing knock out mice deficient in a variety of Zn transporters, including Zip6, Zip7, Zip10 and Zip13. Mast Cell Biology and molecular mechanisms of mast cell functions. We are investigating the mechanistic involvement of mast cells in allergy, inflammation, and autoimmune diseases. Recently, we dissected the degranulation process of mast cells. First, FcεRI stimulation triggers microtubule polymerization and granule translocation to the plasma membrane in a calcium-independent manner. Second, the granules fuse with the plasma membrane in a well-characterized calcium-dependent manner. Furthermore, we showed that the Fyn/ Gab2/RhoA, but not the Lyn/SLP-76 signaling pathways, play a critical role in the calciumindependent microtubule-dependent pathway (Nishida et al., J Cell Biol. 2005). At present, we are especially focused on clarifying the molecular mechanisms of calcium-independent microtubule-dependent granule translocation. Recently, we found that Zn is required for FcεRIinduced granule translocation to the plasma membrane and therefore, Zn chelators could Figure 1 Zinc wave. Bone marrow derived mast cells were stimulated by FcεRI and intracellular fluorescence to measure Zn ion levels were assessed every 5 minutes. be potential new anti-allergic agents. Zn is also required for cytokine production by mast cells (Kabu et al., J Immunology. 2006). In addition, we showed that Zn chelation in mast cells prevented translocation of protein kinase C (PKC) as well as putative downstream events such as the phosphorylation and nuclear translocation of NF-κB, resulting in the decreased production of IL-6 and TNFα. Based on this finding, we are now searching for Zn-associated molecules that regulate granule translocation and cytokine production in mast cells. Very recently, we found that Zn also functions as a second messenger capable of converting an external signal into internal events (Yamasaki et al., J Cell Biol. 2007). When we generated an external signal in mast cells by cross-linking IgE receptors, we observed an internal wave of free Zn released from the vicinity of the ER within several minutes after stimulation (Fig.1). We named this phenomenon the “Zinc wave”. Calcium and activated MAP kinase were necessary for the Zinc wave. Since Zn inhibits tyrosine phosphatases and, in fact, Zn enhanced FcεRI-induced total tyrosine phosphorylation, one possible target of the zinc wave is the tyrosine phosphatases (Fig . 2). The precise origin of the zinc wave and its molecular features remain to be resolved. It is also important to identify authentic targets of the zinc wave. Another important question to be answered is whether the zinc wave is a general phenomenon or is specific to mast cells. Recent publications Yamasaki, S., K. Sakata-Sogawa, A. Hasegawa, T. Suzuki, K. Kabu, E. Sato, T. Kurosaki, S. Yamashita, M. Tokunaga, K. Nishida, T. Hirano. Zinc is a novel intracellular second messenger. J. Cell Biol. 177, 637-645, (2007) Kitamura, H., H. Morikawa., H. Kamon., M. Iguchi., S. Hojyo., T. Fukada., S. Yamashita., T. Kaisho., S. Akira., M. Murakami., T. Hirano. Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nature Immunol. 7, 971-977 (2006) Sawa, S., D. Kamimura, G.-H. Jin, H. Morikawa, H. Kamon, M. Nishihara, K. Ishihara, M. Murakami, and T. Hirano. Autoimmune arthritis associated with mutated IL-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J. Exp. Med. 203,1459-1470, (2006) Kitamura H, Kamon H, Sawa S, Park S-J, Katsunuma N, Ishihara K, Murakami M, Hirano T. IL-6-STAT3 controls intracellular MHC classII ab-dimer level through Cathepsin S activity in dendritic cells. Immunity. 23, 491-502 (2005) Nishida K, Yamasaki S, Ito Y, Kabu K, Hattori K, Tezuka T, Nishizumi H, Kitamura D, Goitsuka R, Geha R.S, Yamamoto T, Yagi T, Hirano T. FcεRI-mediated mast cell degranulation requires calcium-independent microtubuledependent translocation of granules to the plasma membrane. J. Cell Biol. 170, 115-126 (2005) Figure 2 Regulation of the Zinc wave. Zinc wave was regulated by calcium and activated MAP kinase. Free Zn modulates FcεRI-induced signaling pathway such as total tyrosine phosphorylation, one possible target of the zinc wave is the tyrosine phosphatases 67
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Special Advisor Kimishige Ishizaka
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i v Organization Director’s Repor
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Director’s Report This is the fou
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RCAI research retreat program. Prev
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Haruhiko Koseki Good housekeeping A
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Hiroshi Ohno Cell fusion may create
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Tsuneyasu Kaisho Halting the inflam
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Takashi Saito Signaling simplified
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Makio Tokunaga Looking beneath the
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Tomohiro Kurosaki Immune cells stim
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Ichiro Taniuchi How cells switch fr
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Invited Presentations Meeting RIKEN
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The 37th Annual Meeting of the Japa
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14-Nov-2007 Antibodies and their re
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Original Photos of the Cover and Fr
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