研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Asbestos surface provides a niche for oxidative modification. 査読有り国際誌 Open Access

Nagai H, Ishihara T, Lee WH, Ohara H, Okazaki Y, Okawa K, Toyokuni S

Cancer science 102 巻 ( 12 ) 頁： 2118 - 25 2011年12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：Cancer Science

Asbestos is a potent carcinogen associated with increased risks of malignant mesothelioma and lung cancer in humans. Although the mechanism of carcinogenesis remains elusive, the physicochemical characteristics of asbestos play a role in the progression of asbestos-induced diseases. Among these characteristics, a high capacity to adsorb and accommodate biomolecules on its abundant surface area has been linked to cellular and genetic toxicity. Several previous studies identified asbestos-interacting proteins. Here, with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry, we systematically identified proteins from various lysates that adsorbed to the surface of commercially used asbestos and classified them into the following groups: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. The surfaces of crocidolite and amosite, two iron-rich types of asbestos, caused more protein scissions and oxidative modifications than that of chrysotile by in situ-generated 4-hydroxy-2-nonenal. In contrast, we confirmed the intense hemolytic activity of chrysotile and found that hemoglobin attached to chrysotile, but not silica, can work as a catalyst to induce oxidative DNA damage. This process generates 8-hydroxy-2′-deoxyguanosine and thus corroborates the involvement of iron in the carcinogenicity of chrysotile. This evidence demonstrates that all three types of asbestos adsorb DNA and specific proteins, providing a niche for oxidative modification via catalytic iron. Therefore, considering the affinity of asbestos for histones/DNA and the internalization of asbestos into mesothelial cells, our results suggest a novel hypothetical mechanism causing genetic alterations during asbestos-induced carcinogenesis. © 2011 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2011.02087.x

miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. 査読有り国際誌 Open Access

Nishikawa E, Osada H, Okazaki Y, Arima C, Tomida S, Tatematsu Y, Taguchi A, Shimada Y, Yanagisawa K, Yatabe Y, Toyokuni S, Sekido Y, Takahashi T

Cancer research 71 巻 ( 19 ) 頁： 6165 - 73 2011年10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：Cancer Research

Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. ©2011 AACR.

DOI： 10.1158/0008-5472.CAN-11-1020

Age-and sun exposure-dependent differences in 8-hydroxy-2′-deoxyguanosine and <i>N</i><SUP>ε</SUP>-(carboxymethyl)lysine in human epidermis 査読有り国際誌 Open Access

Toyokuni, S; Hirao, A; Wada, T; Nagai, R; Date, A; Yoshii, T; Akatsuka, S; Yamashita, Y; Kawada, A

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION 49 巻 ( 2 ) 頁： 121 - 124 2011年9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：Journal of Clinical Biochemistry and Nutrition

Aging and exposure to sunlight are two major factors in the deterioration of skin function. In this study, thirty-six fixed human skin samples from sun-exposed and unexposed areas from young and old individuals were used to evaluate the localization of oxidative stress according to levels and distribution of 8-hydroxy-2′-deoxyguanosine and N ε- (carboxymethyl)lysine in samples using immunohistochemistry. In the epidermis of the young, negligible amounts of 8-hydroxy-2′-deoxyguanosine and N ε-(carboxymethyl)lysine were detected in unexposed areas, whereas nuclear 8-hydroxy-2′-deoxyguanosine and cytoplasmic N ε-(carboxymethyl)lysine were increased in the lower epidermis in sun-exposed areas. In contrast, the aged presented prominent nuclear 8-hydroxy-2′-deoxyguanosine and nuclear N ε-(carboxymethyl) lysine in the epidermis of unexposed areas, concomitant with dermal increase in N ε-(carboxymethyl)lysine. However, the immunostaining of 8-hydroxy-2′-deoxyguanosine and N ε-(carboxymethyl)lysine revealed a decrease in the epidermis of sun-exposed areas in the aged. These results suggest an age-dependent difference in the adaptation and protective mechanisms of the epidermis against sunlight-associated oxidative stress, thus necessitating distinct standards for evaluation in each age group. Further investigation is warranted to elucidate underlying molecular mechanisms. ©2011 JCBN.

DOI： 10.3164/jcbn.11-05

BMAL1 depletion represses growth of mesothelioma through induction of mitotic catastrophe 査読有り国際共著国際誌

Elshazley, MHKA; Hasegawa, Y; Sato, M; Hase, T; Yoshida, K; Toyokuni, S; Seikido, Y; Yokoi, K; Usami, N; Kondo, M

CANCER RESEARCH 71 巻 2011年9月

MET Amplification is a Molecular Hallmark in Endometriosis-associated Ovarian Clear Cell Carcinoma and Correlates With Worse Prognosis 査読有り国際誌

Yamashita, Y; Yatabe, Y; Akatsuka, S; Kajiyama, H; Kikkawa, F; Takahashi, T; Toyokuni, S

EUROPEAN JOURNAL OF CANCER 47 巻頁： S529 - S529 2011年9月

Elucidation of asbestos-induced mesothelial carcinogenesis toward its prevention 国際誌 Open Access

Jiang L., Toyokuni S.

Genes and Environment 33 巻 ( 1 ) 頁： 4 - 9 2011年8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：Genes and Environment

Human exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in the pleural and abdominal cavity. Despite advancements in the molecular analyses of human cases of DMM and animal models, the understanding of the carcinogenic mechanisms remains still limited. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be integrated as follows; (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of reactive oxygen species (ROS) due to their inability to digest the fibers, and that iron contained in crocidolite and amosite fibers works as a catalyst for the generation of ROS, (2) the "chromosome tangling theory" postulates that asbestos fibers impair the equivalent distribution of chromosomes during mitosis, and (3) the "theory of adsorbing many specific proteins as well as carcinogenic molecules" states that asbestos fibers in vivo concentrate specific proteins or chemicals including the components of cigarette smoke and radioactive chemical element. Recent studies suggest that local iron overload is a key event. Elucidation of the major mechanisms underlying DMM would be helpful for the development of strategies to prevent DMM generation in people who have been exposed to asbestos. © The Japanese Environmental Mutagen Society.

DOI： 10.3123/jemsge.33.4

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Iron as a target of chemoprevention for longevity in humans. 査読有り国際誌

Toyokuni S

Free radical research 45 巻 ( 8 ) 頁： 906 - 17 2011年8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：Free Radical Research

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases. © 2011 Informa UK, Ltd.

DOI： 10.3109/10715762.2011.564170

Dietary Fish Oil Promotes Colonic Apoptosis and Mitochondrial Proton Leak in Oxidatively Stressed Mice 査読有り国際誌 Open Access

Fan, YY; Ran, QT; Toyokuni, S; Okazaki, Y; Callaway, ES; Lupton, JR; Chapkin, RS

CANCER PREVENTION RESEARCH 4 巻 ( 8 ) 頁： 1267 - 74 2011年8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：Cancer Prevention Research

An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2Het, Gpx4Het, and transgenic Gpx4Tg mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4Het > SOD2Het > Wt > Gpx4Tg), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4Het and SOD2Het mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4Tg mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P < 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk. ©2011 AACR.

DOI： 10.1158/1940-6207.CAPR-10-0368

The Human Cytomegalovirus Gene Products Essential for Late Viral Gene Expression Assemble into Prereplication Complexes before Viral DNA Replication 査読有り国際誌 Open Access

Isomura, H; Stinski, MF; Murata, T; Yamashita, Y; Kanda, T; Toyokuni, S; Tsurumi, T

JOURNAL OF VIROLOGY 85 巻 ( 13 ) 頁： 6629 - 6644 2011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：Journal of Virology

The regulation of human cytomegalovirus (HCMV) late gene expression by viral proteins is poorly understood, and these viral proteins could be targets for novel antivirals. HCMV open reading frames (ORFs) UL79, -87, and -95 encode proteins with homology to late gene transcription factors of murine gammaherpesvirus 68 ORFs 18, 24, and 34, respectively. To determine whether these HCMV proteins are also essential for late gene transcription of a betaherpesvirus, we mutated HCMV ORFs UL79, -87, and -95. Cells were infected with the recombinant viruses at high and low multiplicities of infection (MOIs). While viral DNA was detected with the recombinant viruses, infectious virus was not detected unless the wild-type viral proteins were expressed in trans. At a high MOI, mutation of ORF UL79, -87, or -95 had no effect on the level of major immediate-early (MIE) gene expression or viral DNA replication, but late viral gene expression from the UL44, -75, and -99 ORFs was not detected. At a low MOI, preexpression of UL79 or -87, but not UL95, in human fibroblast cells negatively affected the level of MIE viral gene expression and viral DNA replication. The products of ORFs UL79, -87, and -95 were expressed as early viral proteins and recruited to prereplication complexes (pre-RCs), along with UL44, before the initiation of viral DNA replication. All three HCMV ORFs are indispensable for late viral gene expression and viral growth. The roles of UL79, -87, and -95 in pre-RCs for late viral gene expression are discussed. © 2011, American Society for Microbiology.

DOI： 10.1128/JVI.00384-11

YAP TRANSCRIPTION COACTIVATOR INDUCES MALIGNANT MESOTHELIOMA CELL PROLIFERATION BY UP-REGULATING CELL CYCLE PROGRESSION 査読有り国際誌

Mizuno, T; Murakami, H; Fujii, M; Ishiguro, F; Kondo, Y; Akatsuka, S; Toyokuni, S; Yokoi, K; Osada, H; Sekido, Y

JOURNAL OF THORACIC ONCOLOGY 6 巻 ( 6 ) 頁： S707 - S708 2011年6月

[Archives of "comprehensive approach on asbestos-related diseases" supported by the "special coordination funds for promoting science and technology (H18-1-3-3-1)"-- overview of group research project, care and specimen registration, cellular characteristics of mesothelioma and immunological effects of asbestos]. 査読有り Open Access

Otsuki T., Nakano T., Hasegawa S., Okada M., Tsujimura T., Sekido Y., Toyokuni S., Nishimoto H., Fukuoka K., Tanaka F., Kumagai N., Maeda M., Nishimura Y.

Nihon eiseigaku zasshi. Japanese journal of hygiene 66 巻 ( 3 ) 頁： 543 - 552 2011年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Nihon eiseigaku zasshi. Japanese journal of hygiene

The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.

DOI： 10.1265/jjh.66.543

[Mechanisms of asbestos-induced carcinogenesis]. 国際誌 Open Access

Toyokuni S, Jiang L, Hu Q, Nagai H, Okazaki Y, Akatsuka S, Yamashita Y

Nihon eiseigaku zasshi. Japanese journal of hygiene 66 巻 ( 3 ) 頁： 562 - 7 2011年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Nihon eiseigaku zasshi. Japanese journal of hygiene

Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.

DOI： 10.1265/jjh.66.562

Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features

Hirotaka, O; Nishikawa, E; Arima, C; Okazaki, Y; Tomida, S; Tatematsu, Y; Taguchi, A; Shimada, Y; Yanagisawa, K; Toyokuni, S; Sekido, Y; Takahashi, T

CANCER RESEARCH 71 巻 2011年4月

XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. 査読有り国際誌

Yamashita Y, Kajiura D, Tang L, Hasegawa Y, Kinoshita T, Nakamura S, Akatsuka S, Toyokuni S, Mori N

American journal of clinical pathology 135 巻 ( 4 ) 頁： 556 - 64 2011年4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：American Journal of Clinical Pathology

A total of 29 cases of diffuse large B-cell lymphoma initially manifesting in the bone marrow (BM-DLBCL) were analyzed for VH gene sequence, and expression microarray of chemokines and chemokine receptors and immunohistochemical analysis were done. Seminested polymerase chain reaction (PCR) and sequencing analyses of 18 cases revealed that the VH gene usage in 6 cases was restricted to VH3-7, in 3 cases to V H4-34, and in 2 cases to VH4-39, which were all previously reported to be autoreactive. In total, 14 of 18 VH genes were those associated with autoimmune diseases, including VH3-21, V H3-23, and VH3-48. Furthermore, cDNA microarray analysis specific for chemokine and chemokine receptors revealed that chemokine receptor XCR1 expression was significantly elevated in the BM-DLBCL cases (P < 05), which was confirmed by quantitative reverse transcriptase-PCR and immunohistochemical analysis. Expression of the chemokine receptor XCR1 and frequent usage of autoreactive VH genes seem to be distinct characteristics of BM-DLBCL. © American Society for Clinical Pathology.

DOI： 10.1309/AJCPCTDC5PY3LXBP

LATS2 is a tumor suppressor gene of malignant mesothelioma

Murakami H.

Cancer Research 71 巻 ( 3 ) 頁： 873 - 883 2011年2月

LATS2 is a tumor suppressor gene of malignant mesothelioma. Open Access

Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y

Cancer research 71 巻 ( 3 ) 頁： 873 - 83 2011年2月

Stage-specific roles of fibulin-5 during oxidative stress-induced renal carcinogenesis in rats. 査読有り国際誌

Ohara H, Akatsuka S, Nagai H, Liu YT, Jiang L, Okazaki Y, Yamashita Y, Nakamura T, Toyokuni S

Free radical research 45 巻 ( 2 ) 頁： 211 - 20 2011年2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：Free Radical Research

By using a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA), this study performed genome-wide analysis to identify target genes during carcinogenesis. It screened for genes with decreased expression in RCCs, with simultaneous loss of heterozygosity, eventually to focus on the fibulin-5 (fbln5) gene. Oxidative damage via Fe-NTA markedly increased Fbln5 in the proximal tubules. RCCs presented lower levels of Fbln5. However, a fraction of RCCs presenting pulmonary metastasis revealed significantly higher levels of Fbln5 than those without metastasis, accompanied by immunopositivity of RCC cells and myofibroblast proliferation. Experiments revealed that RCC cell lines showed lower expression of fbln5 than its non-transformed counterpart NRK52E, but that fbln5 transfection to RCC cell lines changed neither proliferation nor migration/invasion. The data suggest that Fbln5 plays a role not only in the tissue repair and remodelling after renal tubular oxidative damage but also in RCC metastasis, presumably as a cytokine. © 2011 Informa UK, Ltd.

DOI： 10.3109/10715762.2010.523702

LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma 査読有り

Hideki Murakami, Tetsuya Mizuno, Tetsuo Taniguchi, Makiko Fujii, Futoshi Ishiguro, Takayuki Fukui, Shinya Akatsuka, Yoshitsugu Horio, Toyoaki Hida, Yutaka Kondo, Shinya Toyokuni, Hirotaka Osada, Yoshitaka Sekido

CANCER RESEARCH 71 巻 ( 3 ) 頁： 873 - 883 2011年2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：AMER ASSOC CANCER RESEARCH

Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. Cancer Res; 71(3); 873-83. (C)2011 AACR.

DOI： 10.1158/0008-5472.CAN-10-2164

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CD8+CD122+ regulatory T cells (Tregs) and CD4+ Tregs cooperatively prevent and cure CD4+ cell-induced colitis. 査読有り国際誌 Open Access

Endharti AT, Okuno Y, Shi Z, Misawa N, Toyokuni S, Ito M, Isobe K, Suzuki H

Journal of immunology (Baltimore, Md. : 1950) 186 巻 ( 1 ) 頁： 41 - 52 2011年1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：Journal of Immunology

We identified CD8+CD122+ regulatory T cells (Tregs) and demonstrated their importance in the maintenance of immune homeostasis and in the recovery from experimental autoimmune encephalomyelitis. In this paper, we show that CD8+CD122+ Tregs effectively prevent and cure colitis in a mouse model. In our experiments, colitis was induced in lymphocyte-deficient RAG-2-/- mice by transferring CD4 +CD45RBhigh cells that were excluded with CD4+ Tregs. Cotransfer of CD8+CD122+ cells clearly suppressed the development of colitis, and this suppressive effect was similar to that of CD4+CD45RBlow cells that were mostly CD4+ Tregs. CD8+CD122+ cells obtained from IL-10-/- mice were unable to suppress colitis, indicating that IL-10 is an important effect-transmitting factor in the suppression of colitis. CD8 +CD122+ cells showed a suppressive effect when they were transferred 4 wk after CD4+CD45RBhigh cells, indicating the therapeutic potential of CD8+CD122+ cells. A mixture of CD8+CD122+ cells and CD4+CD45RB low cells was far more effective than single Tregs, indicating the synergistic effect of these Tregs. These overall findings demonstrate the potential role of CD8+ Tregs, and possibly together with CD4 + Tregs, in the medical care of inflammatory bowel disease patients. Copyright © 2010 by The American Association of Immunologists, Inc.

DOI： 10.4049/jimmunol.1000800

3-Morpholinosydnonimine participates in the attenuation of neointima formation via inhibition of annexin A2-mediated vascular smooth muscle cell migration 国際誌

Won, KJ; Lee, P; Jung, SH; Jiang, X; Lee, CK; Lin, HY; Kang, H; Lee, HM; Kim, J; Toyokuni, S; Kim, B

PROTEOMICS 11 巻 ( 2 ) 頁： 193 - 201 2011年1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：Proteomics

3-Morpholinosydnonimine (SIN-1) affects vascular smooth muscle cell migration and proliferation, processes essential for atherosclerosis. However, the mechanism by which SIN-1 exerts these effects has not been elucidated. We used 2-DE followed by MALDI-TOF/TOF MS to identify responses in protein expression to SIN-1 in rat aortic smooth muscle. Platelet-derived growth factor-BB increased cell migration and proliferation in rat aortic smooth muscle cells, and subsequent SIN-1 treatment inhibited it. Administration of SIN-1 in vivo attenuated neointima formation in balloon-injured rat carotid arteries. Proteomic analysis showed that glutathione peroxidase and 40S ribosomal protein S12 were differentially expressed in aortic strips exposed to SIN-1. Expression of annexin A2 was decreased by SIN-1. Platelet-derived growth factor-BB-induced cell migration was increased and inhibited in rat aortic smooth muscle cells with overexpression and knockdown of annexin A2 gene, respectively. The expression of annexin A2 was increased in vascular neointima compared with the intact control, which was inhibited by SIN-1 treatment. These results demonstrate that SIN-1 may attenuate vascular neointima formation by inhibiting annexin A2-mediated migration. Therefore, annexin A2 may be a potential target for therapeutic strategies for atherosclerosis. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI： 10.1002/pmic.200900834

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論文 - 豊國　伸哉