Kiyoshi Takeda

Osaka University, Suika, Ōsaka, Japan

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Publications (230)1908.58 Total impact

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    ABSTRACT: Crosslinking of the immunoglobulin receptor FcεRI activates basophils and mast cells to induce immediate and chronic allergic inflammation. However, it remains unclear how the chronic allergic inflammation is regulated. Here, we showed that ecto-nucleotide pyrophosphatase-phosphodiesterase 3 (E-NPP3), also known as CD203c, rapidly induced by FcεRI crosslinking, negatively regulated chronic allergic inflammation. Basophil and mast cell numbers increased in Enpp3(-/-) mice with augmented serum ATP concentrations. Enpp3(-/-) mice were highly sensitive to chronic allergic pathologies, which was reduced by ATP blockade. FcεRI crosslinking induced ATP secretion from basophils and mast cells, and ATP activated both cells. ATP clearance was impaired in Enpp3(-/-) cells. Enpp3(-/-)P2rx7(-/-) mice showed decreased responses to FcεRI crosslinking. Thus, ATP released by FcεRI crosslinking stimulates basophils and mast cells for further activation causing allergic inflammation. E-NPP3 decreases ATP concentration and suppresses basophil and mast cell activity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 02/2015; 42(2):279-93. DOI:10.1016/j.immuni.2015.01.015 · 19.75 Impact Factor
  • Hisako Kayama, Kiyoshi Takeda
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    ABSTRACT: The mammalian gastrointestinal tract, the site of nutrient digestion and absorption, harbors a dense microbial community. The intestinal immune system can distinguish between symbiotic bacteria and pathogens, and activates pro-inflammatory responses against pathogenic bacteria for host defense while remaining unresponsive to the beneficial microbes and dietary antigens. Abnormal activity of innate immunity, which directs the development of adaptive immunity, causes the onset and/or progression of several inflammatory diseases. Thus, activity of innate immunity is finely regulated in the gut. Inflammatory bowel disease is a chronic inflammatory disorder caused by alteration of several factors, such as host genetics, commensal bacteria and diet-derived compounds and metabolites. In intestinal mucosa, multiple innate immune cells have been identified and some populations play a crucial role in the maintenance of gut homeostasis by preventing inadequate adaptive immune responses while others are implicated in the pathogenesis of inflammatory bowel disease by driving Th1 and Th17 responses. In addition, recent studies demonstrated that dietary components and their metabolites produced by commensal bacteria contribute to the generation of a unique intestinal environment and further regulation of a variety of immune responses. Accordingly, alterations of intestinal microbial composition and perturbation of metabolites can trigger intestinal inflammation by inducing inadequate innate/adaptive immune responses.
    Inflammation and Regeneration 01/2015; 35(1):028-041. DOI:10.2492/inflammregen.35.028
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    ABSTRACT: B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 11/2014; DOI:10.1016/j.immuni.2014.10.016 · 19.75 Impact Factor
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    ABSTRACT: Toxoplasma gondii infection results in co-option and subversion of host cellular signaling pathways. This process involves discharge of T. gondii effector molecules from parasite secretory organelles such as rhoptries and dense granules. We report that the T. gondii polymorphic dense granule protein GRA6 regulates activation of the host transcription factor nuclear factor of activated T cells 4 (NFAT4). GRA6 overexpression robustly and selectively activated NFAT4 via calcium modulating ligand (CAMLG). Infection with wild-type (WT) but not GRA6-deficient parasites induced NFAT4 activation. Moreover, GRA6-deficient parasites failed to exhibit full virulence in local infection, and the treatment of WT mice with an NFAT inhibitor mitigated virulence of WT parasites. Notably, NFAT4-deficient mice displayed prolonged survival, decreased recruitment of CD11b(+) Ly6G(+) cells to the site of infection, and impaired expression of chemokines such as Cxcl2 and Ccl2. In addition, infection with type I parasites culminated in significantly higher NFAT4 activation than type II parasites due to a polymorphism in the C terminus of GRA6. Collectively, our data suggest that GRA6-dependent NFAT4 activation is required for T. gondii manipulation of host immune responses to maximize the parasite virulence in a strain-dependent manner.
    Journal of Experimental Medicine 09/2014; 211(10). DOI:10.1084/jem.20131272 · 13.91 Impact Factor
  • Hisako Kayama, Kiyoshi Takeda
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    ABSTRACT: In a recent paper published in Cell Host & Microbe, Dasgupta et al. (2014) demonstrate that a component of the gut microbiota, Bacteroides fragilis, induces IL-10-producing regulatory T cells by driving TLR2-dependent plasmacytoid dendritic cell activation.
    Molecular cell 04/2014; 54(2):206-7. DOI:10.1016/j.molcel.2014.04.002 · 14.46 Impact Factor
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    ABSTRACT: Gut-associated lymphoid tissues are responsible for the generation of IgA-secreting cells. However, the function of the caecal patch, a lymphoid tissue in the appendix, remains unknown. Here we analyse the role of the caecal patch using germ-free mice colonized with intestinal bacteria after appendectomy. Appendectomized mice show delayed accumulation of IgA(+) cells in the large intestine, but not the small intestine, after colonization. Decreased colonic IgA(+) cells correlate with altered faecal microbiota composition. Experiments using photoconvertible Kaede-expressing mice or adoptive transfer show that the caecal patch IgA(+) cells migrate to the large and small intestines, whereas Peyer's patch cells are preferentially recruited to the small intestine. IgA(+) cells in the caecal patch express higher levels of CCR10. Dendritic cells in the caecal patch, but not Peyer's patches, induce CCR10 on cocultured B cells. Thus, the caecal patch is a major site for generation of IgA-secreting cells that migrate to the large intestine.
    Nature Communications 04/2014; 5:3704. DOI:10.1038/ncomms4704 · 10.74 Impact Factor
  • Makoto Kinoshita, Kiyoshi Takeda
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    ABSTRACT: To maintain a quiescent gut microenvironment, proper regulation of immune responses initiated by pro-inflammatory immune subsets is required. Several types of regulatory T cells are reported to exert pivotal roles in achieving this. Among various types of regulatory T cells, the crucial role of Foxp3(+) Treg cells has been well documented. Furthermore, accumulating evidence demonstrates that both microbial and dietary factors influence the induction and suppressor functions of intestinal Foxp3(+) Treg cells. Foxp3(+) Treg cells are a highly activated T cell subset which responds rapidly to environmental and nutritional stimuli. Thus, sufficient nutrient supply is required to fuel the high energetic status of Foxp3(+) Treg cells for the regulation of intestinal immunity.
    FEBS letters 03/2014; 588(22). DOI:10.1016/j.febslet.2014.03.018 · 3.54 Impact Factor
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    ABSTRACT: IFN-γ mediates cellular innate immunity against an intracellular parasite, Toxoplasma gondii, by inducing immunity-related GTPases such as p47 IFN-γ-regulated GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), which also participate in antibacterial responses via autophagy. An essential autophagy protein, Atg5, was previously shown to play a critical role in anti-T. gondii cell-autonomous immunity. However, the involvement of other autophagy proteins remains unknown. In this study, we show that essential autophagy proteins differentially participate in anti-T. gondii cellular immunity by recruiting IFN-γ-inducible GTPases. IFN-γ-induced suppression of T. gondii proliferation and recruitment of an IRG Irgb6 and GBPs are profoundly impaired in Atg7- or Atg16L1-deficient cells. In contrast, cells lacking other essential autophagy proteins, Atg9a and Atg14, are capable of mediating the anti-T. gondii response and recruiting Irgb6 and GBPs to the parasites. Although IFN-γ also stimulates anti-T. gondii cellular immunity in humans, whether this response requires GBPs and human autophagy proteins remains to be seen. To analyze the role of human ATG16L1 and GBPs in IFN-γ-mediated anti-T. gondii responses, human cells lacking ATG16L1 or GBPs were generated by the Cas9/CRISPR genome-editing technique. Although both ATG16L1 and GBPs are dispensable for IFN-γ-induced inhibition of T. gondii proliferation in the human cells, human ATG16L1 is also required for the recruitment of GBPs. Taken together, human ATG16L1 and mouse autophagy components Atg7 and Atg16L1, but not Atg9a and Atg14, participate in the IFN-γ-induced recruitment of the immunity-related GTPases to the intracellular pathogen.
    The Journal of Immunology 02/2014; 192(7). DOI:10.4049/jimmunol.1302822 · 5.36 Impact Factor
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    ABSTRACT: Although interferon (IFN) signaling induces genes that limit viral infection, many pathogenic viruses overcome this host response. As an example, 2'-O methylation of the 5' cap of viral RNA subverts mammalian antiviral responses by evading restriction of Ifit1, an IFN-stimulated gene that regulates protein synthesis. However, alphaviruses replicate efficiently in cells expressing Ifit1 even though their genomic RNA has a 5' cap lacking 2'-O methylation. We show that pathogenic alphaviruses use secondary structural motifs within the 5'-untranslated region (UTR) of their RNA to alter Ifit1 binding and function. Mutations within the 5'-UTR affecting RNA structural elements enabled restriction by or antagonism of Ifit1 in vitro and in vivo. These results identify an evasion mechanism by which viruses use RNA structural motifs to avoid immune restriction.
    Science 01/2014; 343(6172). DOI:10.1126/science.1248465 · 31.48 Impact Factor
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    ABSTRACT: To clarify the function of osteoclast-like multinuclear cells differentiated from bone marrow-derived macrophages (BMMs) by a combination of tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and to investigate the molecular mechanisms underlying the differentiation. BMMs were stimulated by TNFα and/or IL-6. The cells were then compared with conventional osteoclasts differentiated in vitro by RANKL. An in vitro pit formation assay on dentine slices and an in vivo resorption assay of calvarial bones were performed. We also evaluated the activities and expression levels of NF-κB, c-Fos, and NF-ATc1, which are essential to the differentiation of conventional osteoclasts. Small interfering RNA was used to knock down c-Fos. The effects of genetic ablation of STAT-3 and pharmacologic inhibitors of NF-AT, JAK, and ERK were also studied. Osteoclast-like cell differentiation depended on TNFα and IL-6 and was not inhibited by osteoprotegerin. These differentiated cells were associated with both in vitro and in vivo bone resorption activity. TNFα and IL-6 had a synergistic effect on the activity and expression of c-Fos. Knockdown of c-Fos inhibited the expression of NF-ATc1 and the differentiation of osteoclast-like cells. All of these inhibitors blocked differentiation of the cells in vitro, but surprisingly, the conditional knockout of STAT-3 did not. Tofacitinib also inhibited the bone destruction caused by TNFα and IL-6 in vivo. Our results demonstrate that a combination of the inflammatory cytokines TNFα and IL-6 can induce osteoclast-like cells that have in vitro and in vivo bone-resorptive activity.
    01/2014; 66(1):121-9. DOI:10.1002/art.38218
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    Hisako Kayama, Junichi Nishimura, Kiyoshi Takeda
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    ABSTRACT: The intestinal immune system has an ability to distinguish between the microbiota and pathogenic bacteria, and then activate pro-inflammatory pathways against pathogens for host defense while remaining unresponsive to the microbiota and dietary antigens. In the intestine, abnormal activation of innate immunity causes development of several inflammatory disorders such as inflammatory bowel diseases (IBD). Thus, activity of innate immunity is finely regulated in the intestine. To date, multiple innate immune cells have been shown to maintain gut homeostasis by preventing inadequate adaptive immune responses in the murine intestine. Additionally, several innate immune subsets, which promote Th1 and Th17 responses and are implicated in the pathogenesis of IBD, have recently been identified in the human intestinal mucosa. The demonstration of both murine and human intestinal innate immune subsets contributing to regulation of adaptive immunity emphasizes the conserved innate immune functions across species and might promote development of the intestinal innate immunity-based clinical therapy.
    Immune Network 12/2013; 13(6):227-234. DOI:10.4110/in.2013.13.6.227
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    ABSTRACT: Microbiota have been shown to have a great influence on functions of intestinal epithelial cells (ECs). The role of indole as a quorum-sensing (QS) molecule mediating intercellular signals in bacteria has been well appreciated. However, it remains unknown whether indole has beneficial effects on maintaining intestinal barriers in vivo. In this study, we analyzed the effect of indole on ECs using a germ free (GF) mouse model. GF mice showed decreased expression of junctional complex molecules in colonic ECs. The feces of specific pathogen-free (SPF) mice contained a high amount of indole; however the amount was significantly decreased in the feces of GF mice by 27-fold. Oral administration of indole-containing capsules resulted in increased expression of both tight junction (TJ)- and adherens junction (AJ)-associated molecules in colonic ECs in GF mice. In accordance with the increased expression of these junctional complex molecules, GF mice given indole-containing capsules showed higher resistance to dextran sodium sulfate (DSS)-induced colitis. A similar protective effect of indole on DSS-induced epithelial damage was also observed in mice bred in SPF conditions. These findings highlight the beneficial role of indole in establishing an epithelial barrier in vivo.
    PLoS ONE 11/2013; 8(11):e80604. DOI:10.1371/journal.pone.0080604 · 3.53 Impact Factor
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    ABSTRACT: & Aims: Abnormal activity of innate immune cells and T-helper (Th)17 cells has been implicated in the pathogenesis of autoimmune and inflammatory diseases, including Crohn's disease (CD). Intestinal innate immune (myeloid) cells have been found to induce development of Th17 cells in mice, but it is not clear if this occurs in humans, or in patients with CD. We investigated whether human intestinal lamina propria cells (LPCs) induce development of Th17 cells and whether these have a role in pathogenesis of CD. Normal intestinal mucosa samples were collected from patients with colorectal cancer, and non-inflammed and inflammed regions of mucosa were collected from patients with CD. LPCs were isolated by enzymatic digestion and analyzed for expression of HLA-DR, lineage markers (Lin), CD14, and CD163 using flow cytometry. Among HLA-DR(high) Lin(-) cells, we identified a subset of CD14(+) CD163(low) cells in intestinal LPCs; this subset expressed Toll-like receptor (TLR)2, TLR4, and TLR5 mRNAs and produced interleukin (IL)6, IL1β, and tumor necrosis factor (TNF)α in response to lipopolysaccharide. In vitro co-culture with naïve T cells revealed that CD14(+) CD163(low) cells induced development of Th17 cells. CD14(+) CD163(low) cells from inflamed regions of mucosa of patients with CD expressed high levels of IL6, IL23p19, and TNF mRNAs, and strongly induced Th17 cells. CD14(+) CD163(low) cells from the non-inflamed mucosa of patients with CD also had increased abilities to induce Th17 cells, compared with those from normal intestinal mucosa. CD14(+) CD163(low) cells in intestinal LPCs from normal intestinal mucosa induce differentiation of naïve T cells into Th17 cells; this activity is increased in mucosal samples from patients with CD. These findings show how intestinal myeloid cell types could contribute to pathogenesis of CD and possibly other Th17-associated diseases.
    Gastroenterology 08/2013; 145(6). DOI:10.1053/j.gastro.2013.08.049 · 12.82 Impact Factor
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    ABSTRACT: The interferon-inducible protein with tetratricopeptide (IFIT) family proteins inhibit replication of some viruses by recognizing several types of RNAs including 5' -triphosphate RNA and 5' capped 2' -O unmethylated mRNA. However, it remains unclear how IFITs inhibit replication of some viruses through recognition of RNA. Here, we analyzed mechanisms by which Ifit1 exerts antiviral responses. Replication of a Japanese encephalitis virus (JEV) 2' -O MTase mutant was markedly enhanced in mouse embryonic fibroblasts and macrophages lacking Ifit1. Ifit1 bound 5' -triphosphate RNA, but more preferentially associated with 5' capped 2' -O unmethylated mRNA. Ifit1 inhibited the translation of mRNA and thereby restricted the replication of JEV mutated in 2' -O MTase. Thus, Ifit1 inhibits replication of MTase-defective JEV by inhibiting mRNA translation through direct binding to mRNA 5' structures.
    Journal of Virology 07/2013; DOI:10.1128/JVI.00883-13 · 4.65 Impact Factor
  • Hisako Kayama, Kiyoshi Takeda
    Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 05/2013; 110(5):741-52.
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    ABSTRACT: Intestinal plasma cells predominantly produce immunoglobulin (Ig) A, however, their functional diversity remains poorly characterized. Here we show that murine intestinal IgA plasma cells can be newly classified into two populations on the basis of CD11b expression, which cannot be discriminated by currently known criteria such as general plasma cell markers, B cell origin and T cell dependence. CD11b(+) IgA(+) plasma cells require the lymphoid structure of Peyer's patches, produce more IgA than CD11b(-) IgA(+) plasma cells, proliferate vigorously, and require microbial stimulation and IL-10 for their development and maintenance. These features allow CD11b(+) IgA(+) plasma cells to mediate early-phase antigen-specific intestinal IgA responses induced by oral immunization with protein antigen. These findings reveal the functional diversity of IgA(+) plasma cells in the murine intestine.
    Nature Communications 04/2013; 4:1772. DOI:10.1038/ncomms2718 · 10.74 Impact Factor
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    ABSTRACT: Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor-knockout (Hrh1KO) mice, but not in neuron-specific insulin receptor-knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO, but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.
    Diabetes 03/2013; DOI:10.2337/db12-1701 · 7.90 Impact Factor
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    ABSTRACT: Although the pyrazolone derivative sulpyrine is widely used as an antipyretic analgesic drug, side effects, including fatal shock, have been reported. However, the molecular mechanism underlying such a severe side effect is largely unclear. Here, we report that the transcription factor CREBH that is highly expressed in the liver plays an important role in fatal shock induced by sulpyrine in mice. CREBH-deficient mice were resistant to experimental fatal sulpyrine shock. We found that sulpyrine-induced expression of cytochrome P450 2B (CYP2B) family genes, which are involved in sulpyrine metabolism, in the liver was severely impaired in CREBH-deficient mice. Moreover, introduction of CYP2B in CREBH-deficient liver restored susceptibility to sulpyrine. Furthermore, ectopic expression of CREBH up-regulated CYP2B10 promoter activity, and in vivo knockdown of CREBH in wild-type mice conferred a significant resistance to fatal sulpyrine shock. These data demonstrate that CREBH is a positive regulator of CYP2B in response to sulpyrine administration, which possibly results in fatal shock.
    PLoS ONE 02/2013; 8(2):e55800. DOI:10.1371/journal.pone.0055800 · 3.53 Impact Factor
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    ABSTRACT: Extracellular ATP is released from live cells in controlled conditions, as well as dying cells in inflammatory conditions, and, thereby, regulates T cell responses, including Th17 cell induction. The level of extracellular ATP is closely regulated by ATP hydrolyzing enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases). ENTPDase1/CD39, which is expressed in immune cells, was shown to regulate immune responses by downregulating the ATP level. In this study, we analyzed the immunomodulatory function of ENTPDase7, which is preferentially expressed in epithelial cells in the small intestine. The targeted deletion of Entpd7 encoding ENTPDase7 in mice resulted in increased ATP levels in the small intestinal lumen. The number of Th17 cells was selectively increased in the small intestinal lamina propria in Entpd7(-/-) mice. Th17 cells were decreased by oral administration of antibiotics or the ATP antagonist in Entpd7(-/-) mice, indicating that commensal microbiota-dependent ATP release mediates the enhanced Th17 cell development in the small intestinal lamina propria of Entpd7(-/-) mice. In accordance with the increased number of small intestinal Th17 cells, Entpd7(-/-) mice were resistant to oral infection with Citrobacter rodentium. Entpd7(-/-) mice suffered from severe experimental autoimmune encephalomyelitis, which was associated with increased numbers of CD4(+) T cells producing both IL-17 and IFN-γ. Taken together, these findings demonstrate that ENTPDase7 controls the luminal ATP level and, thereby, regulates Th17 cell development in the small intestine.
    The Journal of Immunology 12/2012; 190(2). DOI:10.4049/jimmunol.1103067 · 5.36 Impact Factor
  • Makoto Kinoshita, Kiyoshi Takeda
    Arerugī = [Allergy] 12/2012; 61(12):1726-8.

Publication Stats

38k Citations
1,908.58 Total Impact Points

Institutions

  • 1996–2014
    • Osaka University
      • • Graduate School of Medicine
      • • Department of Microbiology and Immunology
      • • Department of Host Defense
      • • Immunology Division
      Suika, Ōsaka, Japan
    • Osaka Medical Center and Research Institute for Maternal and Child Health
      Izumi, Ōsaka, Japan
  • 2008–2012
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 2004–2009
    • Kyushu University
      • • Department of Molecular Genetics
      • • Medical Institute of Bioregulation - MIB Hospital
      Hukuoka, Fukuoka, Japan
    • RIKEN
      Вако, Saitama, Japan
    • Wakayama Medical University
      • Department of Physiology
      Wakayama, Wakayama, Japan
    • Kumamoto University
      • Department of Pathology and Experimental Medicine
      Kumamoto, Kumamoto Prefecture, Japan
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
  • 2003–2008
    • Hirosaki University
      • Faculty of Agriculture and Life Sciences
      Khirosaki, Aomori Prefecture, Japan
  • 2005
    • National Cancer Institute (USA)
      • Laboratory of Cellular Oncology
      Maryland, United States
  • 2004–2005
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
  • 2002–2003
    • Institute of Microbial Chemistry
      Edo, Tōkyō, Japan
    • Gunma University
      • Institute for Molecular and Cellular Regulation
      Maebashi, Gunma, Japan
    • The University of Manchester
      • Faculty of Life Sciences
      Manchester, ENG, United Kingdom
  • 1998–2003
    • Hyogo College of Medicine
      • Department of Biochemistry
      Nishinomiya, Hyōgo, Japan