研究者詳細 - 前田　恵

論文 - 前田　恵

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Effect of asbestos exposure on differentiation of cytotoxic T lymphocytes in mixed lymphocyte reaction of human peripheral blood mononuclear cells. 査読国際誌

Kumagai-Takei N, Nishimura Y, au, Maeda M, Hayashi H, Matsuzaki H, Lee S, Hiratsuka J, Otsuki T

American journal of respiratory cell and molecular biology 49 ( 1 ) 28 - 36 2013年7月

Purification and characterization of beta-xylosidase that is active for plant complex type N-glycans from tomato (Solanum lycopersicum): removal of core alpha 1-3 mannosyl residue is prerequisite for hydrolysis of beta 1-2 xylosyl residue 査読国際誌

Daisuke Yokouchi, Natsuko Ono, Kosuke Nakamura, Megumi Maeda, Yoshinobu Kimura

GLYCOCONJUGATE JOURNAL 30 ( 5 ) 463 - 472 2013年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

In this study, we purified and characterized the beta-xylosidase involved in the turnover of plant complex type N-glycans to homogeneity from mature red tomatoes. Purified beta-xylosidase (beta-Xyl'ase Le-1) gave a single band with molecular masses of 67 kDa on SDS-PAGE under a reducing condition and 60 kDa on gelfiltration, indicating that beta-Xyl'ase Le-1 has a monomeric structure in plant cells. The N-terminal amino acid could not be identified owing to a chemical modification. When pyridylaminated (PA-) N-glycans were used as substrates, beta-Xyl'ase Le-1 showed optimum activity at about pH 5 at 40 A degrees C, suggesting that the enzyme functions in a rather acidic circumstance such as in the vacuole or cell wall. beta-Xyl'ase Le-1 hydrolyzed the beta 1-2 xylosyl residue from Man(1)Xyl(1)GlcNAc(2)-PA, Man(1)Xyl(1)Fuc(1)GlcNAc(2)-PA, and Man(2)Xyl(1)Fuc(1)GlcNAc(2)-PA, but not that from Man(3)Xyl(1)GlcNAc(2)-PA or Man(3)Xyl(1)Fuc(1)GlcNAc(2)-PA, indicating that the alpha 1-3 arm mannosyl residue exerts significant steric hindrance for the access of beta-Xyl'ase Le-1 to the xylosyl residue, whereas the alpha 1-3 fucosyl residue exerts little effect. These results suggest that the release of the beta 1-2 xylosyl residue by beta-Xyl'ase Le-1 occurs at least after the removal the alpha-1,3-mannosyl residue in the core trimannosyl unit.

DOI： 10.1007/s10719-012-9441-y

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Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases. 査読国際誌

Nishimura Y, Maeda M, Kumagai-Takei N, Lee S, Matsuzaki H, Wada Y, Nishiike-Wada T, Iguchi H, Otsuki T

Environmental health and preventive medicine 18 ( 3 ) 198 - 204 2013年5月

Exploration of biomarkers for asbestos exposure and occurrence of malignant mesothelioma based on the immunological effects of asbestos.

Matsuzaki H, Lee S, Kumagai-Takei N, Hayashi H, Miura Y, Chen Y, Maeda M, Yamamoto S, Hatayama T, Nishimura Y, Otsuki T

Journal of Data Mining Genomics Proteomics S2 001 2013年

アスベストの免疫毒性学的側面と病態への関与

大槻剛巳, 前田恵, 武井直子, 松崎秀紀, 李順姫, 西村泰光

日本毒性学会学術年会 40.1 1114 2013年

記述言語：日本語出版者・発行元：日本毒性学会

アスベストによる発癌性については，含有する鉄による酸化ストレス，繊維状物質としての物理的なDNA損傷，そしてその他の発癌物質の吸着などが考えられる。一方，アスベストは珪酸（SiO2)の金属塩であり，珪酸曝露症例（珪肺症）にて自己免疫疾患が多く合併することや，その実験的検証から，アスベストもまた免疫毒性あるいは免疫担当細胞への作用が想定される。さらにアスベスト曝露者の合併症として悪性中皮腫などの発癌，初期曝露からの長期の潜伏期を考えると，抗腫瘍免疫の減衰などを惹起している可能性がある。我々は，アスベストの免疫担当細胞への影響ならびに抗腫瘍免疫との関連について，検討を加えている。細胞株モデル，健常人末梢血から採取した新鮮免疫担当細胞，あるいは曝露者（胸膜プラークや悪性中皮腫症例）の末梢血のリンパ球の解析を行ってきている。T細胞では，細胞株や，健常人由来細胞にて長期曝露によってアスベストが誘導するアポトーシスに抵抗性を獲得することが判明し，その機序として，Src-kinase，IL-10，STAT3，BCL-2の関与が判明した。さらにこれらの細胞では，抗腫瘍免疫にも重要なCXCR3発現やIFNγ産生の低下も認められた。制御性T細胞では細胞株モデルにて可用性因子であるIL-10，TGFβの産生過剰とともに細胞間接着による反応性T細胞の活性化抑制能の増強も確認された。制御性T細胞ではマスタージーンであるFoxP3を制御するFOXO1の発現低下と，それに伴う細胞周期の異調節なども観察されている。また，CD8+細胞障害性T細胞においても，実験系での分化誘導・増殖時のアスベスト曝露での抑制が判明した。一方，NK細胞においても，細胞内シグナリングの減弱とともに，機能発現活性化受容体の発現減弱が認められ，特にNKp46分子については，アスベスト曝露症例においても，その殺細胞能との相関が認められた。さらなる検討とともに，曝露や担癌の指標あるいは予防的観点からのこれらの成果の応用も期待される。

DOI： 10.14869/toxpt.40.1.0.1114.0

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Structural features of N-glycans of seaweed glycoproteins: predominant occurrence of high-mannose type N-glycans in marine plants. 査読国際誌

Yoshiie T, Maeda M, Kimura M, Hama Y, Uchida M, Kimura Y

Bioscience, biotechnology, and biochemistry 76 ( 10 ) 1996 - 1998 2012年10月

Resistance to asbestos-induced apoptosis with continuous exposure to crocidolite on a human T cell. 査読国際誌

Maeda M, Yamamoto S, Chen Y, Kumagai-Takei N, Hayashi H, Matsuzaki H, Lee S, Hatayama T, Miyahara N, Katoh M, Hiratsuka J, Nishimura Y, Otsuki T

The Science of the total environment 429 174 - 82 2012年7月

Environmental factors producing autoimmune dysregulation--chronic activation of T cells caused by silica exposure. 査読国際誌

Lee S, Hayashi H, Maeda M, Chen Y, Matsuzaki H, Takei-Kumagai N, Nishimura Y, Fujimoto W, Otsuki T

Immunobiology 217 ( 7 ) 743 - 8 2012年7月

Review of reduced tumor immunity caused by asbestos exposure to immunocompetent cells such as T and NK cells. 査読

Otsuki T, Lee S, Kumagai-Takei N, Miyahara N, Katoh M, Yamamoto S, Hatayama T, Matsuzaki H, Nishimura Y, Maeda M, Hayashi H, Hirastuka J, Chen Y

Open Access Scientific reports 1 ( 8 ) open access 2012年

Asbestos-induced cellular and molecular alteration of immunocompetent cells and their relationship with chronic inflammation and carcinogenesis. 査読国際誌

Matsuzaki H, Maeda M, Lee S, Nishimura Y, Kumagai-Takei N, Hayashi H, Yamamoto S, Hatayama T, Kojima Y, Tabata R, Kishimoto T, Hiratsuka J, Otsuki T

Journal of biomedicine & biotechnology 2012 492608 - 492608 2012年

Decreased CXCR3 expression in CD4+ T cells exposed to asbestos or derived from asbestos-exposed patients. 査読国際誌

Megumi Maeda, Yasumitsu Nishimura, Hiroaki Hayashi, Naoko Kumagai, Ying Chen, Shuko Murakami, Yoshie Miura, Jun-ichi Hiratsuka, Takumi Kishimoto, Takemi Otsuki

American journal of respiratory cell and molecular biology 45 ( 4 ) 795 - 803 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Asbestos causes malignant tumors such as lung cancer and malignant mesothelioma (MM). To determine whether asbestos exposure causes reduction of antitumor immunity, we established an in vitro T-cell line model of low-dose and continuous exposure to asbestos using an human adult T-cell leukemia virus-1 immortalized human polyclonal T-cell line, MT-2, and revealed that MT-2 cells exposed continuously to asbestos showed resistance to asbestos-induced apoptosis. In addition, the cells presented reduction of surface CXCR3 chemokine receptor expression and IFN-γ production. In this study, to confirm that these findings are suitable for clinical translation, surface CXCR3 and IFN-γ expression were analyzed using freshly isolated human CD4(+) T cells derived from healthy donors and patients with pleural plaque (PP) or MM. The results revealed that CXCR3 and IFN-γ expression in the ex vivo model were reduced in some cases. Additionally, CXCR3 expression in CD4(+) T cells from PPs and MMs was significantly reduced compared with that from healthy donors, and CD4(+) T cells from patients with MMs exhibited a marked reduction in IFN-γ mRNA levels after stimulation in vitro. Moreover, CD4(+)CXCR3(+) T cells in lymphocytes from MMs showed a tendency for an inverse correlation with its ligand CXCL10/IP10 in plasma. These findings show reduction of antitumor immune function in asbestos-exposed patients and indicate that CXCR3, IFN-γ, and CXCL10/IP10 may be candidates to detect and monitor disease status.

DOI： 10.1165/rcmb.2010-0435OC

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川崎医科大学における大学連携、産学官連携等、対外活動について：その2

大槻剛巳, 小笠原康夫, 柏原直樹, 佐藤稔, 大澤裕, 矢田豊隆, 毛利聡, 山内明, 武井直子, 前田恵, 西村泰光, 小野寺昇, 望月精一, 茅野功, 川西礼美, 福永仁夫

川崎医学会誌 37 47 - 59 2011年9月

Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbestos in a human T-cell line, MT-2. 査読国際誌

Megumi Maeda, Yasumitsu Nishimura, Hiroaki Hayashi, Naoko Kumagai, Ying Chen, Shuko Murakami, Yoshie Miura, Jun-ichi Hiratsuka, Takumi Kishimoto, Takemi Otsuki

American journal of respiratory cell and molecular biology 45 ( 3 ) 470 - 9 2011年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Because patients with silicosis who are chronically exposed to silica particles develop not only pulmonary fibrosis, but also complications involving autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, exposure to asbestos may affect the human immune system. This immunologic effect may impair antitumor immune function because cancer complications such as lung cancer and malignant mesothelioma are found in patients exposed to asbestos. To elucidate the antitumor immune status caused by CD4(+) T cells exposed to asbestos, an in vitro T-cell model of long-term and low-level exposure to chrysotile asbestos was established from a human adult T-cell leukemia virus-1-immortalized human polyclonal T cell line, MT-2, and the resulting six sublines showed resistance to asbestos-induced apoptosis after more than 8 months of continuous exposure. The results of DNA microarray analysis showed that the expression of 139 genes was altered by long-term and low-level exposure to asbestos, and the profile was almost similar among the six sublines when compared with the original MT-2 cells that had never been exposed to asbestos. Pathway and network analysis indicated a down-regulation of IFN-γ signaling and expression of CXC chemokine receptor 3 (CXCR3) in the sublines, whereas ELISA and flow cytometry analysis demonstrated a reduction in Th1-related IFN-γ production and cell-surface CXCR3 expression. These findings suggest that chronic exposure to asbestos may reduce antitumor immune status in CD4(+) T cells, and that an in vitro T-cell model may be useful in identifying molecules related to the impairment of antitumor immune function.

DOI： 10.1165/rcmb.2010-0213OC

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Effects of environmental substance on the human immune system - Reduction of tumor immunity induced by asbestos exposure

Naoko Kumagai, Megumi Maeda, Hidenori Matsuzaki, Suni Lee, Yasumitsu Nishimura, Takemi Otsuki

Biotherapy 25 ( 4 ) 739 - 746 2011年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Similar to the silica which causes dysregulation of autoimmunity as well as pulmonary fibrosis, asbestos, which is mineral silicate including iron, magnesium or calcium attached to the core silica molecule, SiO2 may affect the human immune system. Considering malignant complications of asbestos-exposed patients such as mesothelioma and lung cancer, asbestos is assumed to lower tumor immunity. The effects of asbestos on tumor immunity have been investigated with this in mind. It was found that natural killer (NK) cell activity was reduced in correspondence with the surface expression level of NKp46, one of the activating receptors of the NK cell. The proliferation and differentiation of cytotoxic T lymphocytes (CTL) were inhibited during induction of effector/memory CTL from naïve CD8+ T cells by culturing with allo-antigen supplemented with chrysotile-asbestos. In addition, tumor immunity-related molecules such as interferon (IFN) -γ and the CXCR3 chemokine receptor, were reduced by asbestos exposure using the T cell line, MT-2. Furthermore, activation-inhibitory functions such as the CD4 +CD25+FoxP3+ regulatory T cell possessing the MT-2 cell line, was enhanced by asbestos exposure. All of these findings suggested that asbestos exposure lowered tumor immunity. In addition, some of these findings were confirmed in asbestos-exposed patients. Reduction of tumor immunity caused by exposure to asbestos may make it easier to develop asbestos-inducing malignant tumors in the patients with asbestos exposure.

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Quick detection of overexpressed genes caused by myeloma-specific chromosomal translocations using multiplex RT-PCR. 査読国際誌

San San Htwe, Megumi Maeda, Rui Matsumoto, Natsumi Sakamoto, Shuko Murakami, Shoko Yamamoto, Minako Katoh, Naoko Kumagai, Hiroaki Hayashi, Yasumitsu Nishimura, Mitsugi Ohkura, Hideho Wada, Masafumi Taniwaki, Takashi Sugihara, Takemi Otsuki

International journal of molecular medicine 27 ( 6 ) 789 - 94 2011年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Multiple myeloma (MM) is a malignancy of the plasmocyte and is associated with various symptoms such as anemia, immunodeficiency, bone lesions and kidney insufficiency. Although prognosis was poor until some years ago, recent advances that introduced newer molecular targeting agents such as bortezomib and thalidomide have resulted in a better prognosis for MM. However, clinical manifestations and the relationship between cellular and molecular findings, including chromosomal translocation and the related overexpression of oncogenes such as CCND1 (cyclin D1) and FGFR3 (fibroblast growth factor receptor 3), remain unclear. It has been reported that a specific translocation may influence the prognosis of MM. Although translocations and overexpressed genes should be examined in ordinary clinical investigations, limited definitive assays for translocation involve the use of FISH (fluorescent in situ hybridization) or SKY (special karyotypic) methods. We therefore, attempted to establish a quick detection method for major translocated genes such as FGFR3, CCND1, CCND3 and MAF using multiplex RT-PCR (MP-RT-PCR). MP-RT-PCR can be performed within several to 24 h after bone marrow samples are taken. Two of 21 bone marrow blood samples from MM patients were analyzed using MP-RT-PCR and double-color FISH, and the results of both methods were compatible. Future utilization and elaboration of this method may help our understanding of the cell biology and clinical features of MM.

DOI： 10.3892/ijmm.2011.648

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珪酸の免疫影響と自己寛容の破綻査読

李順姫, 林宏明, 前田恵, 熊谷直子, 松﨑秀紀, 草加勝康, 浦上更三, 藤本亘, 大槻剛巳

臨床環境医学 20 40 - 53 2011年6月

Double-Knockout of Putative Endo-beta-N-acetylglucosaminidase (ENGase) Genes in Arabidopsis thaliana: Loss of ENGase Activity Induced Accumulation of High-Mannose Type Free N-Glycans Bearing N,N '-Acetylchitobiosyl Unit 査読国際誌

Yoshinobu Kimura, Yuki Takeoka, Masami Inoue, Megumi Maeda, Kazuhito Fujiyama

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 75 ( 5 ) 1019 - 1021 2011年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：TAYLOR & FRANCIS LTD

Endo-beta-N-acetylglucosaminidase (ENGase) is involved in the production of high-mannose type free N-glycans during plant development and fruit maturation. In a previous study (K. Nakamura et al. Biosci. Biotechnol. Biochem., 73, 461-464 (2009)), we identified the tomato ENGase gene and found that gene expression remained relatively constant. In the present study, we constructed an Arabidopsis thaliana mutant in which the expression of two putative ENGase genes was suppressed. The mutant showed no ENGase activity, but produced high-mannose type free N-glycans carrying the N,N'-acetylchitobiosyl unit that is produced by peptide:N-glycanase, indicating that both these genes encode Arabidopsis ENGase.

DOI： 10.1271/bbb.110148

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ヒト免疫担当細胞への環境中物質の影響―アスベスト曝露による腫瘍免疫減衰― 査読

熊谷直子, 前田恵, 松﨑秀紀, 李順姫, 西村泰光, 大槻剛巳

Biotherapy 25 ( 4 ) 739 - 746 2011年4月

Dysregulation of autoimmunity caused by silica exposure and alteration of Fas-mediated apoptosis in T lymphocytes derived from silicosis patients 査読

Otsuki T, Hayashi H, Nishimura Y, Hyodo F, Maeda M, Kumagai N, Miura Y, Kusaka M, Urakami K

Int J Immunopath Pharmacol 24 ( 1S ) 11S - 16S 2011年1月

Suppressive effect of asbestos on cytotoxicity of human NK cells 査読

Nishimura Y, Kumagai N, Maeda M, Hayashi H, Fukuoka K, Nakano T, Miura Y, Hiratsuka J, Otsuki T

Int J Immunopath Pharmacol 24 ( 1S ) 5S - 10S 2011年1月

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