Noriko Toyama-Sorimachi

Publications (26)206.19 Total impact

• Article: Ly49Q Positively Regulates Type I IFN Production by Plasmacytoid Dendritic Cells in an Immunoreceptor Tyrosine-Based Inhibitory Motif-Dependent Manner.

  Mir Munir A Rahim, Lee-Hwa Tai, Angela D Troke, Ahmad Bakur Mahmoud, Elias Abou-Samra, Justin G Roy, Amelia Mottashed, Nicholas Ault, Chloe Corbeil, Marie-Line Goulet, Haggag S Zein, Melisa Hamilton-Valensky, Gerald Krystal, William G Kerr, Noriko Toyama-Sorimachi, Andrew P Makrigiannis
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  ABSTRACT: Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN during the initial immune response to viral infection. Ly49Q, a C-type lectin-like receptor specific for MHC-I, possesses a cytoplasmic ITIM and is highly expressed on murine pDC. Using Ly49Q-deficient mice, we show that, regardless of strain background, this receptor is required for maximum IFN-α production by pDC. Furthermore, Ly49Q expression on pDC, but not myeloid dendritic cells, is necessary for optimal IL-12 secretion, MHC-II expression, activation of CD4+ T cell proliferation, and nuclear translocation of the master IFN-α regulator IFN regulatory factor 7 in response to TLR9 agonists. In contrast, the absence of Ly49Q did not affect plasmacytoid dendritic cell-triggering receptor expressed on myeloid cells expression or pDC viability. Genetic complementation revealed that IFN-α production by pDC is dependent on an intact tyrosine residue in the Ly49Q cytoplasmic ITIM. However, pharmacological inhibitors and phosphatase-deficient mice indicate that Src homology 2 domain-containing phosphatase 1 (SHP)-1, SHP-2, and SHIP phosphatase activity is dispensable for this function. Finally, we observed that Ly49Q itself is downregulated on pDC in response to CpG exposure in an ITIM-independent manner. In conclusion, Ly49Q enhances TLR9-mediated signaling events, leading to IFN regulatory factor 7 nuclear translocation and expression of IFN-I genes in an ITIM-dependent manner that can proceed without the involvement of SHP-1, SHP-2, and SHIP.
  The Journal of Immunology 03/2013; · 5.79 Impact Factor
• Article: The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice.

  Shigemi Sasawatari, Tadashi Okamura, Eiji Kasumi, Kaori Tanaka-Furuyama, Rieko Yanobu-Takanashi, Senji Shirasawa, Norihiro Kato, Noriko Toyama-Sorimachi
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  ABSTRACT: Solute carrier family 15 (SLC15) A4 is a proton-coupled histidine and oligopeptide cotransporter expressed by the immune and nervous systems and associated with disorders such as inflammatory bowel diseases and systemic lupus erythematosus. High levels of SLC15A4 transcripts were observed in human antigen-presenting cells, including dendritic cells, activated macrophages, and B cells. However, the roles of SLC15A4 in the immune regulation are not known. We investigated the function of SLC15A4 in the innate immune system. We created SLC15A4-deficient (SLC15A4(-/-)) mice and compared Toll-like receptor 9 and NOD1-dependent innate immune responses between SLC15A4(-/-) and control (SLC15A4(+/+)) mice. SLC15A4 deficiency impaired CpG-induced production of interleukin-12, interleukin-15, and interleukin-18 by dendritic cells. Correspondingly, SLC15A4(-/-) mice developed a less severe form of Th1-dependent colitis than SLC15A4(+/+) mice. Increased lysosomal histidine, in the absence of SLC15A4, appears to negatively regulate Toll-like receptor 9 function by inhibiting the proteolytic activities of cathepsins B and L. SLC15A4(-/-) mice also had a severe defect in NOD1-dependent cytokine production, indicating that SLC15A4 functions as a transporter of the NOD1 ligand. SLC15A4 promotes colitis through Toll-like receptor 9 and NOD1-dependent innate immune responses. Histidine homeostasis within intracellular compartments is important for eliciting effective innate immune responses.
  Gastroenterology 01/2011; 140(5):1513-25. · 11.68 Impact Factor
• Source

  Available from: PubMed Central

  Article: The innate immune system in host mice targets cells with allogenic mitochondrial DNA.

  Kaori Ishikawa, Noriko Toyama-Sorimachi, Kazuto Nakada, Mami Morimoto, Hirotake Imanishi, Mariko Yoshizaki, Shigemi Sasawatari, Mamoru Niikura, Keizo Takenaga, Hiromichi Yonekawa, Jun-Ichi Hayashi
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  ABSTRACT: Mitochondrial DNA (mtDNA) has been proposed to be involved in respiratory function, and mtDNA mutations have been associated with aging, tumors, and various disorders, but the effects of mtDNA imported into transplants from different individuals or aged subjects have been unclear. We examined this issue by generating trans-mitochondrial tumor cells and embryonic stem cells that shared the syngenic C57BL/6 (B6) strain-derived nuclear DNA background but possessed mtDNA derived from allogenic mouse strains. We demonstrate that transplants with mtDNA from the NZB/B1NJ strain were rejected from the host B6 mice, not by the acquired immune system but by the innate immune system. This rejection was caused partly by NK cells and involved a MyD88-dependent pathway. These results introduce novel roles of mtDNA and innate immunity in tumor immunology and transplantation medicine.
  Journal of Experimental Medicine 10/2010; 207(11):2297-305. · 13.85 Impact Factor
• Article: Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy.

  Koichi Ojima, Yukiko Kawabata, Harumi Nakao, Kazuki Nakao, Naoko Doi, Fujiko Kitamura, Yasuko Ono, Shoji Hata, Hidenori Suzuki, Hiroyuki Kawahara, [......], Coen Ottenheijm, Siegfried Labeit, Henk Granzier, Noriko Toyama-Sorimachi, Michiko Sorimachi, Koichi Suzuki, Tatsuya Maeda, Keiko Abe, Atsu Aiba, Hiroyuki Sorimachi
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  ABSTRACT: Limb-girdle muscular dystrophy type 2A (LGMD2A) is a genetic disease that is caused by mutations in the calpain 3 gene (CAPN3), which encodes the skeletal muscle-specific calpain, calpain 3 (also known as p94). However, the precise mechanism by which p94 functions in the pathogenesis of this disease remains unclear. Here, using p94 knockin mice (termed herein p94KI mice) in which endogenous p94 was replaced with a proteolytically inactive but structurally intact p94:C129S mutant protein, we have demonstrated that stretch-dependent p94 distribution in sarcomeres plays a crucial role in the pathogenesis of LGMD2A. The p94KI mice developed a progressive muscular dystrophy, which was exacerbated by exercise. The exercise-induced muscle degeneration in p94KI mice was associated with an inefficient redistribution of p94:C129S in stretched sarcomeres. Furthermore, the p94KI mice showed impaired adaptation to physical stress, which was accompanied by compromised upregulation of muscle ankyrin-repeat protein-2 and hsp upon exercise. These findings indicate that the stretch-induced dynamic redistribution of p94 is dependent on its protease activity and essential to protect muscle from degeneration, particularly under conditions of physical stress. Furthermore, our data provide direct evidence that loss of p94 protease activity can result in LGMD2A and molecular insight into how this could occur.
  The Journal of clinical investigation 08/2010; 120(8):2672-83. · 15.39 Impact Factor
• Source

  Available from: Hiroyuki Sorimachi

  Article: Calpain 8/nCL-2 and calpain 9/nCL-4 constitute an active protease complex, G-calpain, involved in gastric mucosal defense.

  Shoji Hata, Manabu Abe, Hidenori Suzuki, Fujiko Kitamura, Noriko Toyama-Sorimachi, Keiko Abe, Kenji Sakimura, Hiroyuki Sorimachi
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  ABSTRACT: Calpains constitute a superfamily of Ca2+-dependent cysteine proteases, indispensable for various cellular processes. Among the 15 mammalian calpains, calpain 8/nCL-2 and calpain 9/nCL-4 are predominantly expressed in the gastrointestinal tract and are restricted to the gastric surface mucus (pit) cells in the stomach. Possible functions reported for calpain 8 are in vesicle trafficking between ER and Golgi, and calpain 9 are implicated in suppressing tumorigenesis. These highlight that calpains 8 and 9 are regulated differently from each other and from conventional calpains and, thus, have potentially important, specific functions in the gastrointestinal tract. However, there is no direct evidence implicating calpain 8 or 9 in human disease, and their properties and physiological functions are currently unknown. To address their physiological roles, we analyzed mice with mutations in the genes for these calpains, Capn8 and Capn9. Capn8(-/-) and Capn9(-/-) mice were fertile, and their gastric mucosae appeared normal. However, both mice were susceptible to gastric mucosal injury induced by ethanol administration. Moreover, the Capn8(-/-) stomach showed significant decreases in both calpains 9 and 8, and the same was true for Capn9(-/-). Consistent with this finding, in the wild-type stomach, calpains 8 and 9 formed a complex we termed "G-calpain," in which both were essential for activity. This is the first example of a "hybrid" calpain complex. To address the physiological relevance of the calpain 8 proteolytic activity, we generated calpain 8:C105S "knock-in" (Capn8(CS/CS)) mice, which expressed a proteolytically inactive, but structurally intact, calpain 8. Although, unlike the Capn8(-/-) stomach, that of the Capn8(CS/CS) mice expressed a stable and active calpain 9, the mice were susceptible to ethanol-induced gastric injury. These results provide the first evidence that both of the gastrointestinal-tract-specific calpains are essential for gastric mucosal defense, and they point to G-calpain as a potential target for gastropathies caused by external stresses.
  PLoS Genetics 07/2010; 6(7):e1001040. · 8.69 Impact Factor
• Article: The Ly49Q receptor plays a crucial role in neutrophil polarization and migration by regulating raft trafficking.

  Shigemi Sasawatari, Mariko Yoshizaki, Choji Taya, Aya Tazawa, Kaori Furuyama-Tanaka, Hiromichi Yonekawa, Taeko Dohi, Andrew P Makrigiannis, Takehiko Sasazuki, Kayo Inaba, Noriko Toyama-Sorimachi
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  ABSTRACT: Neutrophils rapidly undergo polarization and directional movement to infiltrate the sites of infection and inflammation. Here, we show that an inhibitory MHC I receptor, Ly49Q, was crucial for the swift polarization of and tissue infiltration by neutrophils. During the steady state, Ly49Q inhibited neutrophil adhesion by preventing focal-complex formation, likely by inhibiting Src and PI3 kinases. However, in the presence of inflammatory stimuli, Ly49Q mediated rapid neutrophil polarization and tissue infiltration in an ITIM-domain-dependent manner. These opposite functions appeared to be mediated by distinct use of effector phosphatase SHP-1 and SHP-2. Ly49Q-dependent polarization and migration were affected by Ly49Q regulation of membrane raft functions. We propose that Ly49Q is pivotal in switching neutrophils to their polarized morphology and rapid migration upon inflammation, through its spatiotemporal regulation of membrane rafts and raft-associated signaling molecules.
  Immunity 02/2010; 32(2):200-13. · 21.64 Impact Factor
• Article: Ly49Q, an ITIM-bearing NK receptor, positively regulates osteoclast differentiation.

  Mikihito Hayashi, Tomoki Nakashima, Tatsuhiko Kodama, Andrew P Makrigiannis, Noriko Toyama-Sorimachi, Hiroshi Takayanagi
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  ABSTRACT: Osteoclasts, multinucleated cells that resorb bone, play a key role in bone remodeling. Although immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling is critical for osteoclast differentiation, the significance of immunoreceptor tyrosine-based inhibitory motif (ITIM) has not been well understood. Here we report the function of Ly49Q, an Ly49 family member possessing an ITIM motif, in osteoclastogenesis. Ly49Q is selectively induced by receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) stimulation in bone marrow-derived monocyte/macrophage precursor cells (BMMs) among the Ly49 family of NK receptors. The knockdown of Ly49Q resulted in a significant reduction in the RANKL-induced formation of tartrate-resistance acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a decreased expression of osteoclast-specific genes such as Nfatc1, Tm7sf4, Oscar, Ctsk, and Acp5. Osteoclastogenesis was also significantly impaired in Ly49Q-deficient cells in vitro. The inhibitory effect of Ly49Q-deficiency may be explained by the finding that Ly49Q competed for the association of Src-homology domain-2 phosphatase-1 (SHP-1) with paired immunoglobulin-like receptor-B (PIR-B), an ITIM-bearing receptor which negatively regulates osteoclast differentiation. Unexpectedly, Ly49Q deficiency did not lead to impaired osteoclast formation in vivo, suggesting the existence of a compensatory mechanism. This study provides an example in which an ITIM-bearing receptor functions as a positive regulator of osteoclast differentiation.
  Biochemical and Biophysical Research Communications 02/2010; 393(3):432-8. · 2.48 Impact Factor
• Article: Spatiotemporal regulation of intracellular trafficking of Toll-like receptor 9 by an inhibitory receptor, Ly49Q.

  Mariko Yoshizaki, Aya Tazawa, Eiji Kasumi, Shigemi Sasawatari, Kenji Itoh, Taeko Dohi, Takehiko Sasazuki, Kayo Inaba, Andrew P Makrigiannis, Noriko Toyama-Sorimachi
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  ABSTRACT: Toll-like receptor (TLR) 9 recognizes unmethylated microorganismal cytosine guanine dinucleotide (CpG) DNA and elicits innate immune responses. However, the regulatory mechanisms of the TLR signaling remain elusive. We recently reported that Ly49Q, an immunoreceptor tyrosine-based inhibitory motif-bearing inhibitory receptor belonging to the natural killer receptor family, is crucial for TLR9-mediated type I interferon production by plasmacytoid dendritic cells. Ly49Q is expressed in plasmacytoid dendritic cells, macrophages, and neutrophils, but not natural killer cells. In this study, we showed that Ly49Q regulates TLR9 signaling by affecting endosome/lysosome behavior. Ly49Q colocalized with CpG in endosome/lysosome compartments. Cells lacking Ly49Q showed a disturbed redistribution of TLR9 and CpG. In particular, CpG-induced tubular endolysosomal extension was impaired in the absence of Ly49Q. Consistent with these findings, cells lacking Ly49Q showed impaired cytokine production in response to CpG-oligodeoxynucleotide. Our data highlight a novel mechanism by which TLR9 signaling is controlled through the spatiotemporal regulation of membrane trafficking by the immunoreceptor tyrosine-based inhibitory motif-bearing receptor Ly49Q.
  Blood 07/2009; 114(8):1518-27. · 9.90 Impact Factor
• Source

  Available from: Silvia M Vidal

  Article: Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC.

  Lee-Hwa Tai, Marie-Line Goulet, Simon Belanger, Noriko Toyama-Sorimachi, Nassima Fodil-Cornu, Silvia M Vidal, Angela D Troke, Daniel W McVicar, Andrew P Makrigiannis
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  ABSTRACT: Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2K(b). Conversely, CpG-ODN-dependent IFN-alpha production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2K(b) ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo.
  Journal of Experimental Medicine 01/2009; 205(13):3187-99. · 13.85 Impact Factor
• Article: Dose-dependent differential regulation of cytokine secretion from macrophages by fractalkine.

  Noriko Mizutani, Toshiharu Sakurai, Takahiro Shibata, Koji Uchida, Jun Fujita, Rei Kawashima, Yuki I Kawamura, Noriko Toyama-Sorimachi, Toshio Imai, Taeko Dohi
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  ABSTRACT: Although expression of the fractalkine (CX3CL1, FKN) is enhanced in inflamed tissues, it is detected at steady state in various organs such as the intestine, and its receptor CX3CR1 is highly expressed in resident-type dendritic cells and macrophages. We hypothesized that FKN might regulate the inflammatory responses of these cells. Therefore, murine macrophages were pretreated with FKN and then stimulated with LPS. We found that macrophages pretreated with 0.03 nM FKN but not with 3 nM FKN secreted 50% less TNF-alpha than did cells treated with LPS alone. Cells treated with 0.03 nM FKN and LPS also showed reduced phosphorylation of ERK1/2 and reduced NF-kappaB p50 subunit. Interestingly, the p65 subunit of NF-kappaB was translocated to the nuclei but redistributed to the cytoplasm in the early phase by forming a complex with peroxisome proliferator-activated receptor (PPAR) gamma. Exogenous 15-deoxy-Delta(12,14)-prostaglandin J2, a natural ligand for PPAR-gamma, also induced redistribution of p65 with decreased TNF-alpha secretion after LPS challenge. Pretreatment with 0.03 nM but not 3 nM FKN increased the cellular levels of 15-deoxy-Delta(12,14)-prostaglandin J2 as well as mRNA of PPAR-gamma. Requirement of PPAR-gamma for the effect of 0.03 nM FKN was confirmed by small interfering RNA of PPAR-gamma. In contrast, pretreatment with 3 nM FKN induced higher levels of IL-23 compared with cells pretreated with 0.03 nM FKN and produced TNF-alpha in a CX3CR1-dependent manner. These dose-dependent differential effects of FKN establish its novel role in immune homeostasis and inflammation.
  The Journal of Immunology 01/2008; 179(11):7478-87. · 5.79 Impact Factor
• Source

  Available from: uottawa.ca

  Article: Recognition of H-2K(b) by Ly49Q suggests a role for class Ia MHC regulation of plasmacytoid dendritic cell function.

  Lee-Hwa Tai, Marie-Line Goulet, Simon Belanger, Angela D Troke, Aaron G St-Laurent, Aruz Mesci, Noriko Toyama-Sorimachi, James R Carlyle, Andrew P Makrigiannis
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  ABSTRACT: Ly49Q is a member of the polymorphic Ly49 family of NK cell receptors that displays both a high degree of conservation and a unique expression pattern restricted to myeloid lineage cells, including plasmacytoid dendritic cells (pDC). The function and ligand specificity of Ly49Q are unknown. Here, we use reporter cell analysis to demonstrate that a high-affinity ligand for Ly49Q is present on H-2(b), but not H-2(d), H-2(k), H-2(q), or H-2(a)-derived tumor cells and normal cells ex vivo. The ligand is peptide-dependent and MHC Ia-like, as revealed by its functional absence on cells deficient in TAP-1, beta(2)m, or H-2K(b)D(b) expression. Furthermore, Ly49Q is specific for H-2K(b), as the receptor binds peptide-loaded H-2K(b) but not H-2D(b) complexes, and Ly49Q recognition can be blocked using anti-K(b) but not anti-D(b) mAb. Greater soluble H-2K(b) binding to ligand-deficient pDC also suggests cis interactions of Ly49Q and H-2K(b). These results demonstrate that Ly49Q efficiently binds H-2K(b) ligand, and suggest that pDC function, like that of NK cells, is regulated by classical MHC Ia molecules. MHC recognition capability by pDC has important implications for the role of this cell type during innate immune responses.
  Molecular Immunology 05/2007; 44(10):2638-46. · 2.90 Impact Factor
• Article: Inhibition of CCL1-CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions.

  Akiyoshi Hoshino, Yuki I Kawamura, Masato Yasuhara, Noriko Toyama-Sorimachi, Kenji Yamamoto, Akihiro Matsukawa, Sergio A Lira, Taeko Dohi
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  ABSTRACT: Peritoneal adhesions are a significant complication of surgery and visceral inflammation; however, the mechanism has not been fully elucidated. The aim of this study was to clarify the mechanism of peritoneal adhesions by focusing on the cell trafficking and immune system in the peritoneal cavity. We investigated the specific recruitment of peritoneal macrophages (PMphi) and their expression of chemokine receptors in murine models of postoperative and postinflammatory peritoneal adhesions. PMphi aggregated at the site of injured peritoneum in these murine models of peritoneal adhesions. The chemokine receptor CCR8 was up-regulated in the aggregating PMphi when compared with naive PMphi. The up-regulation of CCR8 was also observed in PMphi, but not in bone marrow-derived Mphi, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PMphi and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. Cell aggregation involving PMphi and PMCs was induced in vitro in the presence of CCL1. CCL1 also up-regulated mRNA levels of plasminogen activator inhibitor-1 in both PMphi and PMCs. CCR8 gene-deficient mice or mice treated with anti-CCL1-neutralizing Ab exhibited significantly reduced postoperational peritoneal adhesion. Our study now establishes a unique autocrine activation system in PMphi and the mechanism for recruitment of PMphi together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity, which triggers peritoneal adhesions.
  The Journal of Immunology 04/2007; 178(8):5296-304. · 5.79 Impact Factor
• Article: IL-13 receptor alpha2 promotes epithelial cell regeneration from radiation-induced small intestinal injury in mice.

  Rei Kawashima, Yuki I Kawamura, Rie Kato, Noriko Mizutani, Noriko Toyama-Sorimachi, Taeko Dohi
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  ABSTRACT: The cytokines interleukin (IL)-4 and IL-13 have pleiotropic effects on a variety of cell types and impact both pathologic changes and tissue remodeling. The aim of this study was to clarify the roles of IL-13 receptor alpha2 (IL-13Ralpha2), which is the high-affinity decoy receptor for IL-13, in gastrointestinal tract epithelial cell turnover and repair. We have compared the regenerative process following mucosal damage induced by whole-body 3-Gy X-ray irradiation of wild-type (WT) and IL-4 receptor alpha gene-deficient (IL-4R(-/-)) mice. Then we treated mice with IL-13Ralpha2 human immunoglobulin (Ig) chimeric protein. Up-regulation of mRNA levels for IL-13 in NK cells in the lamina propria was seen after irradiation of WT mice. Concomitant with vigorous epithelial cell division in the jejunum following irradiation, expression of the IL-13Ralpha2 dramatically increased in myofibroblasts and fibroblasts. In contrast, epithelial cell repair was delayed in IL-4R(-/-) mice, which did not show transient up-regulation of IL-13Ralpha2, although up-regulation of IL-13 was seen. Addition of IL-13 but not IL-4 to primary cultures of small intestine from both WT and IL-4R(-/-) mice induced epithelial cell damage. Treatment of IL-4R(-/-) mice with IL-13Ralpha2-Ig resulted in increased numbers of dividing epithelial cells and improved tissue repair after irradiation. Further, treatment with IL-13Ralpha2-Ig increased numbers of microcolonies of regenerating epithelial cells in the intestine of WT mice after severe damage induced by 12-Gy irradiation. The IL-13Ralpha2 is a major regulatory factor involved in the regeneration of epithelial cells in the gastrointestinal tract.
  Gastroenterology 07/2006; 131(1):130-41. · 11.68 Impact Factor
• Article: Predominant T helper type 2-inflammatory responses promote murine colon cancers.

  Emi Osawa, Atsushi Nakajima, Toshio Fujisawa, Yuki I Kawamura, Noriko Toyama-Sorimachi, Hitoshi Nakagama, Taeko Dohi
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  ABSTRACT: Colon cancer is one of the most serious complications of inflammatory bowel diseases, especially ulcerative colitis (UC). Previous studies have shown that characteristic immunological event during inflammation in UC is the expression of T helper-type 2 (Th2) cell-derived cytokines. In this study, we investigated the influence of a predominant Th2-type cytokine response in colitis on carcinogen-induced colon tumors. Wild type (WT), interferon gamma (IFN-gamma) gene deficient (-/-) [Th2 dominant] or interleukin (IL)-4(-/-) [Th1-dominant] mice of BALB/c background were used in this study. To compare tumor formation, mice were given the carcinogen azoxymethane (AOM) and intrarectal administration of trinitrobenzene sulfonic acid (TNBS), to induce colitis. Thirty-three weeks after initial treatment, the total colon was examined. When IFN-gamma(-/-) mice were treated with AOM and TNBS, significantly higher number of tumors were seen (8.4 +/- 1.7) than in WT (3.3 +/- 2.9) or IL-4(-/-) (3.1 +/- 3.4) mice, which received identical treatments. A separate set of experiment, using less doses of AOM and TNBS also showed the higher frequency of tumor formation in IFN-gamma(-/-) mice than in IL-4(-/-) mice. Histologically, the tumors were well- or moderately-differentiated adenocarcinomas. No invasion into the submucosal or serosal layers of the intestine was seen. In immunohistological staining, some tumors in IFN-gamma(-/-) mice showed distinct nuclear expression of beta-catenin, in contrast to the strong membrane staining seen in tumors of IL-4(-/-) mice. In conclusion, colonic inflammation associated with Th2-dominant cytokine responses enhanced the formation of malignant neoplasms.
  International Journal of Cancer 06/2006; 118(9):2232-6. · 5.44 Impact Factor
• Article: Stomach-specific calpain, nCL-2, localizes in mucus cells and proteolyzes the beta-subunit of coatomer complex, beta-COP.

  Shoji Hata, Suguru Koyama, Hiroyuki Kawahara, Naoko Doi, Tatsuya Maeda, Noriko Toyama-Sorimachi, Keiko Abe, Koichi Suzuki, Hiroyuki Sorimachi
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  ABSTRACT: Calpain is a Ca2+-regulated cytosolic protease. Mammals have 14 calpain genes, half of which are predominantly expressed in specific organ(s); the rest are expressed ubiquitously. A defect in calpains causes lethality/pathogenicity, indicating their physiological indispensability. nCL-2/calpain-8a was identified as a stomach-specific calpain, whose physiological functions are unclear. To elucidate these, we characterized nCL-2 in detail. Unexpectedly, nCL-2 was localized strictly to the surface mucus cells in the gastric epithelium and the mucus-secreting goblet cells in the duodenum. Yeast two-hybrid screening identified several nCL-2-interacting molecules. Of these, the beta-subunit of coatomer complex (beta-COP) occurs in the stomach pit cells and is proteolyzed by nCL-2 in vitro. Furthermore, beta-COP and nCL-2 co-expressed in COS7 cells co-localized in the Golgi, and Ca2+-ionophore stimulation caused the proteolysis of beta-COP near the linker region, resulting in the dissociation of beta-COP from the Golgi. These results strongly suggest novel functions for nCL-2 that involve the membrane trafficking of mucus cells via interactions with coat protein.
  Journal of Biological Chemistry 05/2006; 281(16):11214-24. · 4.77 Impact Factor
• Article: Stomach-specific Calpain, nCL-2, Localizes in Mucus Cells and Proteolyzes the β-Subunit of Coatomer Complex, β-COP

  Shoji Hata, Suguru Koyama, Hiroyuki Kawahara, Naoko Doi, Tatsuya Maeda, Noriko Toyama-Sorimachi, Keiko Abe, Koichi Suzuki, Hiroyuki Sorimachi
  [show abstract] [hide abstract]
  ABSTRACT: Calpain is a Ca2+-regulated cytosolic protease. Mammals have 14 calpain genes, half of which are predominantly expressed in specific organ(s); the rest are expressed ubiquitously. A defect in calpains causes lethality/pathogenicity, indicating their physiological indispensability. nCL-2/calpain-8a was identified as a stomach-specific calpain, whose physiological functions are unclear. To elucidate these, we characterized nCL-2 in detail. Unexpectedly, nCL-2 was localized strictly to the surface mucus cells in the gastric epithelium and the mucus-secreting goblet cells in the duodenum. Yeast two-hybrid screening identified several nCL-2-intracting molecules. Of these, the β-subunit of coatomer complex (β-COP) occurs in the stomach pit cells and is proteolyzed by nCL-2 in vitro. Furthermore, β-COP and nCL-2 co-expressed in COS7 cells co-localized in the Golgi, and Ca2+-ionophore stimulation caused the proteolysis of β-COP near the linker region, resulting in the dissociation of β-COP from the Golgi. These results strongly suggest novel functions for nCL-2 that involve the membrane trafficking of mucus cells via interactions with coat protein.
  Journal of Biological Chemistry 04/2006; 281(16):11214-11224. · 4.77 Impact Factor
• Article: Introduction of Sd(a) carbohydrate antigen in gastrointestinal cancer cells eliminates selectin ligands and inhibits metastasis.

  Yuki I Kawamura, Rei Kawashima, Ryuko Fukunaga, Kazunari Hirai, Noriko Toyama-Sorimachi, Makoto Tokuhara, Toshio Shimizu, Taeko Dohi
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  ABSTRACT: The Sd(a) blood group carbohydrate structure is expressed in the normal gastrointestinal mucosa. We reported previously that the expression of Sd(a) carbohydrate structures and beta1,4-N-acetylgalactosaminyltransferase (beta1,4GalNAcT) activity responsible for Sd(a) synthesis were remarkably decreased in cancer lesions of the gastrointestinal tract. In this study, we found that Sd(a) antigen was expressed mainly in chief cells of normal stomach but not in cancer tissue by immunohistologic staining. In separated gastric mucosal cells, the Sd(a) glycolipids and beta1,4GalNAcT activity were concentrated in a fraction that contained chief cells as a major population. We cloned the cDNA encoding the glycosyltransferase that catalyzes the synthesis of Sd(a) (Sd(a)-beta1,4GalNAcT). Introduction of this cloned cDNA into KATO III gastric or HT29 colonic cancer cell lines, which originally expressed the E-selectin ligands, sialyl Lewis(x) and sialyl Lewis(a), resulted in a marked increase in cell-surface expression of Sd(a) along with the concomitant total loss of both sialyl Lewis(x) and sialyl Lewis(a). Both KATO III and HT29 cells transfected with the Sd(a)-beta1,4GalNAcT gene showed significantly decreased adhesion to activated human umbilical vein endothelial cells when compared with mock-transfected cells. Sd(a) determinants showed no direct binding to Siglec-3, -5, -7, and -9. These Sd(a)-beta1,4GalNAcT-transfected cells showed strikingly reduced metastatic potential in vivo when compared with mock-transfected cells. In summary, forced expression of Sd(a) carbohydrate determinant caused remarkable elimination of carbohydrate ligands for selectin and reduced metastasis of human gastrointestinal tract cancer cells.
  Cancer Research 08/2005; 65(14):6220-7. · 7.86 Impact Factor
• Article: Development of murine plasmacytoid dendritic cells defined by increased expression of an inhibitory NK receptor, Ly49Q.

  Yoshiki Omatsu, Tomonori Iyoda, Yukino Kimura, Akiko Maki, Masaki Ishimori, Noriko Toyama-Sorimachi, Kayo Inaba
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  ABSTRACT: Plasmacytoid dendritic cells (PDCs) are defined in mice by a unique combination of markers: CD11c, B220, and Ly6C/G. We have reported previously that PDCs express Ly49Q, a lectin-type killer cell inhibitory receptor. We now find that different expression levels of Ly49Q define sequential developmental stages of PDCs in bone marrow. Although PDCs in spleen and lymph nodes express high levels of Ly49Q, a significant portion of CD11c(+)B220(+) PDCs in bone marrow lack Ly49Q, as well as the CD4 and MHC II. Purified Ly49Q(-) marrow PDCs spontaneously up-regulate Ly49Q after overnight culture without cell proliferation and acquire most features of typical PDCs in spleen. When exposed to TLR ligands, such as CpG-oligodeoxynucleotide and hemagglutinating virus of Japan (Sendai virus), Ly49Q(-) PDCs increase CD86 and MHC class II expression but produce less IFN-alphabeta, IL-6, and IL-12p70 than Ly49Q(+) PDCs, although they are able to produce comparable amounts of TNF-alpha. However, interestingly, Ly49Q(-) PDCs do not produce TNF-alpha in response to the TLR2 ligand, Pam3SCK(4), whereas Ly49Q(+) PDCs did. Therefore, Ly49Q is a new marker to identify a precursor form of PDCs that participates in innate immunity.
  The Journal of Immunology 07/2005; 174(11):6657-62. · 5.79 Impact Factor
• Article: Inhibitory NK receptor Ly49Q is expressed on subsets of dendritic cells in a cellular maturation- and cytokine stimulation-dependent manner.

  Noriko Toyama-Sorimachi, Yoshiki Omatsu, Atsuko Onoda, Yusuke Tsujimura, Tomonori Iyoda, Akiko Kikuchi-Maki, Hiroyuki Sorimachi, Taeko Dohi, Shinsuke Taki, Kayo Inaba, Hajime Karasuyama
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  ABSTRACT: Ly49Q is a member of the Ly49 family that is expressed on Gr-1+ cells but not on NK and NKT cells. Ly49Q appears to be involved in regulating cytoskeletal architectures through ITIM-mediated signaling. We provide evidence that dendritic cells (DCs) of certain maturational states expressed Ly49Q, and that IFN-alpha plays an important role in its regulation. Freshly prepared murine plasmacytoid pre-DCs as well as Flt3L-induced plasmacytoid pre-DCs expressed Ly49Q, whereas freshly prepared myeloid DCs did not. However, GM-CSF-induced myeloid DCs showed low levels of Ly49Q expression, and this was significantly enhanced by IFN-alpha. In contrast, other cytokines and ligands for TLRs such as TNF-alpha, IL-6, LPS, and CpG-ODN had little or no effect on Ly49Q expression. Plasmacytoid pre-DCs in all mouse strains examined expressed Ly49Q. Constitutive expression of Ly49Q on myeloid DCs was observed in three restricted mouse strains including 129, NZB, and NZW. As can be seen in other Ly49 family members, Ly49Q expression was affected by MHC class I expression. At the same time, Ly49Q possessed polymorphisms, including at least three alleles. The polymorphic residues lay within the stalk and carbohydrate recognition domain, and two of them, in loop 3 and loop 6 of the carbohydrate recognition domain, are located in the region implicated in the interaction of Ly49A with H-2D(d). Therefore, depending on IFN-alpha, our results imply that Ly49Q serves a role for the biological functions of certain DC subsets through recognition of MHC class I or related molecules.
  The Journal of Immunology 05/2005; 174(8):4621-9. · 5.79 Impact Factor
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  Available from: Yoshinori Nagai

  Article: Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.

  Hisaaki Shinohara, Akane Inoue, Noriko Toyama-Sorimachi, Yoshinori Nagai, Tomoharu Yasuda, Hiromi Suzuki, Reiko Horai, Yoichiro Iwakura, Tadashi Yamamoto, Hajime Karasuyama, Kensuke Miyake, Yuji Yamanashi
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  ABSTRACT: Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras-Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-kappaB, resulting in hyperproduction of TNF-alpha and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-alpha and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-alpha production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity.
  Journal of Experimental Medicine 03/2005; 201(3):333-9. · 13.85 Impact Factor