ごあいさつ
－ 死細胞のリサイクル －
免疫制御学研究室教授
田中正人
生体には不要となった細胞や有害な細胞に細胞死を誘導し、これを排除するしくみが存在します。 この細胞死はアポトーシスと呼ばれ、発生や再生過程における不要細胞や、癌細胞やウイルス感染細胞の排除に重要な役割を果たしています。 このアポトーシスが起こると、その死骸はマクロファージ等の食細胞により速やかに貪食されます。
これまでこの死細胞貪食は、廃棄物である死細胞を処理するための単なる“ゴミ掃除”であると考えられてきました。 しかし我々の研究により、マクロファージは貪食した死細胞を分解・再利用することにより、様々な免疫応答を制御していることが分かってきました。 生体内では毎日何百万もの細胞が死を迎えていると考えられるので、マクロファージのこの仕事は、生体内での究極のリサイクルと言えるかもしれません。
我々はこれまでに、この死細胞貪食による免疫制御を応用して、自己免疫疾患の発症を予防できることを示しました。 最近では、がん死細胞によるがん増殖抑制現象に注目し、がん死細胞を貪食してがん免疫を活性化する“死細胞担当マクロファージ”を同定し、本現象の分子細 胞生物学的メカニズムを明らかにしました。 免疫制御学研究室では食細胞による免疫制御機構の解明をさらに進めるとともに、得られた知見を基に自己免疫疾患や悪性腫瘍の新しい治療法の開発を目指して います。
ご興味のある方はどうぞ見学にいらしてください。
プロジェクト紹介
死細胞貪食による免疫制御機構の解明
ヒトは数十兆個の多種多様な細胞で成り立っているが、その発生の過程で不要となった細胞は、細胞死により排除される。この細胞死はアポトーシスと呼ばれ、 細胞に内在する自殺プログラムの実行により起こる。また体内で癌化した細胞やウイルスに感染した細胞も、その初期の段階でアポトーシスにより積極的に排除 されている。
このように、体内では毎日多くの細胞がアポトーシスにより排除されているにもかかわらず、生体内をどんなに注意深く観察しても、その死骸を見つけることは 極めて難しい。これはアポトーシスを起こした細胞の死骸が、マクロファージ や樹状細胞といった食細胞により速やかに貪食され、処理されているためである。このマクロファージによる死細胞の貪食は、アポトーシスそれ自体と同様に、 生体の恒常性の維持に重要な役割を果たしていると考えられている。
貪食の分子機構
マクロファージ等の食細胞は死細胞を速やかに貪食するが、生きている細胞は決して貪食しない。このことから食細胞は生細胞上にはなく、死細胞表面上にのみ存在する分子を特異的に認識する機構を有していると考えられる。我々は、以前にこの現象に関与 する分子として、Milk Fat Globule EGF Factor 8 (MFG-E8)と呼ばれる分子を同定した。MFG-E8はアポトーシス細胞上に出現するフォスファチジルセリンに特異的に結合し、さらにRGD配列依存 的に食細胞表面のαvβ3インテグリンに結合する。MFG-E8はアポトーシス細胞と食細胞を橋渡し死細胞の貪食を促進する機能を有することが分かった。
死細胞貪食の生理的意義
生体内における死細胞貪食は、死細胞の出現後極めて迅速に起こるが、この現象の生理的、病理的意義は何であろうか。 MFG-E8欠損マウスでは脾臓やリンパ節の胚中心での死細胞の貪食に異常が見られるが、加齢に伴って高率に血清中の抗核抗体や抗 DNA抗体が陽性となり、腎臓の糸球体における免疫グロブリンの沈着や蛋白尿といった糸球体腎炎の所見を呈する。また死細胞貪食を抑制する作用を持つ変異 MFG-E8タンパクをマウスに繰り返し静注すると、やはり血清中に抗リン脂質抗体や抗核抗体が出現する。これらの知見より死細胞の貪食は自己に対する免 疫寛容状態を維持するのに重要な役割を果たしており、死細胞貪食の異常が自己免疫疾患発症の一因である可能性が示された。
死細胞貪食による免疫制御法の開発
マクロファージ等の食細胞は、貪食した死細胞を有効活用することにより、積極的に免疫寛容や活性化を誘導することが明らかになってきた。我々はこの機構を 応用し、死細胞を 用いた自己免疫疾患や癌の治療法の開発に成功した。さらに、この死細胞投与による免疫制御に関与する特殊なマクロファージを同定し、その機能解析を行っている。
メンバー
教授 田中 正人
mtanaka(a)toyaku.ac.jp
准教授 浅野 謙一
asanok(a)toyaku.ac.jp
助教 四元 聡志
yotumoto(a)toyaku.ac.jp
※メールアドレスの(a)は@に置き換えて下さい
| 研究員 | 小川 慶（東京大学耳鼻科） |
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| D3 | 澁谷 拓未 |
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| D2 | 菊池 健太 |
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| M2 | 岡田 まりか / 徳弘 拓斗 / 佐藤 晴香 |
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| M1 | 石井 伶奈 / 久保田 浩明 / 髙栁 葉月 丸山 珠里 / 吉川 歩里 |
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| 卒業研究生 | 13 名在籍 |
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| 研究補助員 | 大川 和佳子 |
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| 事務補助員 | 河名 ますみ |
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業績
Publication List 教授 田中 正人
2018
Shinde PV, Xu HC, Maney SK, Kloetgen A, Namineni S, Zhuang Y, Honke N, Shaabani N, Bellora N, Doerrenberg M, Trilling M, Pozdeev VI, van Rooijen N, Scheu S, Pfeffer K, Crocker PR, Tanaka M, Duggimpudi S, Knolle P, Heikenwalder M, Ruland J, Mak TW, Brenner D, Pandyra AA, Hoell JI, Borkhardt A, Haussinger D, Lang KS, Lang PA. Tumor Necrosis Factor-Mediated Survival of CD169(+) Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection. J Virol 92; 2018. 
Kikuchi K, Iida M, Ikeda N, Moriyama S, Hamada M, Takahashi S, Kitamura H, Watanabe T, Hasegawa Y, Hase K, Fukuhara T, Sato H, Kobayashi EH, Suzuki T, Yamamoto M, Tanaka M, Asano K. Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation. J Immunol 201; 635-51, 2018.
Ikeda N, Asano K, Kikuchi K, Uchida Y, Ikegami H, Takagi R, Yotsumoto S, Shibuya T, Makino-Okamura C, Fukuyama H, Watanabe T, Ohmuraya M, Araki K, Nishitai G, Tanaka M. Emergence of immunoregulatory Ym1(+)Ly6C(hi) monocytes during recovery phase of tissue injury. Sci Immunol 3; 2018.
Deguchi Y, Nishina T, Asano K, Ohmuraya M, Nakagawa Y, Nakagata N, Sakuma T, Yamamoto T, Araki K, Mikami T, Tanaka M, Nakano H. Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice. Biochem Biophys Res Commun 505; 453-9, 2018.
2017
Yotsumoto S, Muroi Y, Chiba T, Ohmura R, Yoneyama M, Magarisawa M, Dodo K, Terayama N, Sodeoka M, Aoyagi R, Arita M, Arakawa S, Shimizu S, Tanaka M. Hyperoxidation of ether-linked phospholipids accelerates neutrophil extracellular trap formation. Sci Rep 7; 16026, 2017.
Wang D, Li Q, Yang Y, Hao S, Han X, Song J, Yin Y, Li X, Tanaka M, Qiu CH. Macrophage Subset Expressing CD169 in Peritoneal Cavity-Regulated Mucosal Inflammation Together with Lower Levels of CCL22. Inflammation 40; 1191-203, 2017.
Piao X, Yamazaki S, Komazawa-Sakon S, Miyake S, Nakabayashi O, Kurosawa T, Mikami T, Tanaka M, Van Rooijen N, Ohmuraya M, Oikawa A, Kojima Y, Kakuta S, Uchiyama Y, Tanaka M, Nakano H. Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum. Hepatology 65; 237-52, 2017.
Perez OA, Yeung ST, Vera-Licona P, Romagnoli PA, Samji T, Ural BB, Maher L, Tanaka M, Khanna KM. CD169(+) macrophages orchestrate innate immune responses by regulating bacterial localization in the spleen. Sci Immunol 2; eaah5520, 2017.
Li Q, Wang D, Hao S, Han X, Xia Y, Li X, Chen Y, Tanaka M, Qiu CH. CD169 Expressing Macrophage, a Key Subset in Mesenteric Lymph Nodes Promotes Mucosal Inflammation in Dextran Sulfate Sodium-Induced Colitis. Front Immunol 8; 669, 2017.
Itoh M, Suganami T, Kato H, Kanai S, Shirakawa I, Sakai T, Goto T, Asakawa M, Hidaka I, Sakugawa H, Ohnishi K, Komohara Y, Asano K, Sakaida I, Tanaka M, Ogawa Y. CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis. JCI Insight 2; 2017.
Arai Y, Takahashi D, Asano K, Tanaka M, Oda M, Ko SBH, Ko MSH, Mandai S, Nomura N, Rai T, Uchida S, Sohara E. Salt suppresses IFNgamma inducible chemokines through the IFNgamma-JAK1-STAT1 signaling pathway in proximal tubular cells. Sci Rep 7; 46580, 2017.
2016
Matsushita N, Suzuki M, Ikebe E, Nagashima S, Inatome R, Asano K, Tanaka M, Matsushita M, Kondo E, Iha H, Yanagi S.‘Regulation of B cell differentiation by the ubiquitin-binding protein TAX1BP1.’Scientific Reports. 2016 Aug 12;6:31266. doi: 10.1038/srep31266.
Yoshida T, Tsujioka M, Honda S, Tanaka M, Shimizu S. Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF. Oncotarget. 2016 Jun 7;7(23):34420-9. doi: 10.18632/oncotarget.8883
2015
Tanaka M, Nishitai G. Immune Regulation by Dead Cell Clearance.Curr Top Microbiol Immunol. 2015 Aug 18.
Karasawa K, Asano K, Moriyama S, Ushiki M, Monya M, Iida M, Kuboki E, Yagita H, Uchida K, Nitta K, and Tanaka M. ‘Vascular-resident CD169-Positive Monocytes and macrophages Control Neutrophil Accumulation in the Kidney with Ischemia-reperfusion Injury.’ Journal of American Society of Nephrology. 26:896-906, 2015. doi: 10.1681/ASN.2014020195.
Motomura Y, Kanno S, Asano K, Tanaka M, Hasegawa Y, Katagiri H, Saito T, Hara H, Nishio H, Hara T, Yamasaki S. ‘Identification of Pathogenic Cardiac CD11c+ Macrophages in Nod1-Mediated Acute Coronary Arteritis.’ Arterioscler Thromb Vasc Biol. 35(6):1423-33, 2015. doi: 10.1161/ATVBAHA.114.304846.
Inoue H, Matsuzaki Y, Tanaka A, Hosoi K, Ichimura K, Arasaki K, Wakana Y, Asano K, Tanaka M, Okuzaki D, Yamamoto A, Tani K, Tagaya M. ‘γ-SNAP stimulates disassembly of endosomal SNARE complexes and regulates endocytic trafficking pathways.’ J Cell Sci.128(15):2781-94, 2015. doi: 10.1242/jcs.158634.
Asano K, Takahashi N, Ushiki M, Monya M, Aihara F, Kuboki E, Moriyama S, Iida M, Kitamura H, Qiu CH, Watanabe T, Tanaka M. ‘Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes.’ Nat Commun. 21;6:7802, 2015.doi: 10.1038/ncomms8802.
2014
Yonekawa, A., Saijo, S., Hoshino, Y., Miyake, Y., Ishikawa, E., Suzukawa, M., Inoue, H., Tanaka, M., Yoneyama, M., Oh-Hora, M., Akashi, K., and Yamasaki, S. Dectin-2 Is a Direct Receptor for Mannose-Capped Lipoarabinomannan of Mycobacteria. Immunity. 41(3):402-13.2014
Taguchi K, Okada A, Kitamura H, Yasui T, Naik T, Hamamoto S, Ando R, Mizuno K, Kawai N, Tozawa K, Asano K, Tanaka M, Miyoshi I, Kohri K. Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation. J Am Soc Nephrol. 25(8) : 1680-1697, 2014. Published online before print February 27, 2014, doi: 10.1681/ASN.2013060675
Ravishankar B, Shinde R, Liu H, Chaudhary K, Bradley J, P. Lemos H, Chandler P, Tanaka M, Munn DH, Mellor AL, McGaha L, Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc Natl Acad Sci USA. 111(11):4215-4220, 2014. doi: 10.1073/pnas.1320924111. Epub 2014 Mar 3. Proceedings of the National Academy of Sciences of the United States of America.
2013
Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, Garcia-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M. Tissue-Resident Macrophages Self-Maintain Locally throughout Adult Life with Minimal Contribution from Circulating Monocytes. Immunity, 38: 792-804, 2013. . doi: 10.1016/j.immuni.2013.04.004.
Chow A, Huggins M, Ahmed J, Hashimoto D, Lucas D, Kunisaki Y, Pinho S, Leboeuf M, Noizat C, van Rooijen N, Tanaka M, Zhao ZJ, Bergman A, Merad M, Frenette PS. CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med, 19: 429-436, 2013.
2012
Ravishankar B, Liu H, Shinde R, Chandler P, Baban B, Tanaka M, Munn DH, Mellor AL, Karlsson MC, McGaha TL. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A, 109: 3909-3914, 2012.
Mizukami S, Kajiwara C, Tanaka M, Kaisho T, Udono H. Differential MyD88/IRAK4 requirements for cross-priming and tumor rejection induced by heat shock protein 70-model antigen fusion protein. Cancer Sci, 103: 851-859, 2012.
2011
Muppidi JR, Arnon TI, Bronevetsky Y, Veerapen N, Tanaka M, Besra GS, Cyster JG. Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone. J Exp Med, 208: 1941-1948, 2011.
Honke N, Shaabani N, Cadeddu G, Sorg UR, Zhang DE, Trilling M, Klingel K, Sauter M, Kandolf R, Gailus N, van Rooijen N, Burkart C, Baldus SE, Grusdat M, Lohning M, Hengel H, Pfeffer K, Tanaka M, Haussinger D, Recher M, Lang PA, Lang KS. Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. Nat Immunol, 13: 51-57, 2011.
Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D, Scheiermann C, Battista M, Leboeuf M, Prophete C, van Rooijen N, Tanaka M, Merad M, Frenette PS. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med, 208: 261-271, 2011.
Asano K, Nabeyama A, Miyake Y, Qiu CH, Kurita A, Tomura M, Kanagawa O, Fujii S, Tanaka M. CD169-Positive Macrophages Dominate Antitumor Immunity by Crosspresenting Dead Cell-Associated Antigens. Immunity, 34: 85-95, 2011.
2010
Tanaka M, Asano K, Qiu CH. Immune regulation by apoptotic cell clearance. Ann N Y Acad Sci, 1209: 37-42, 2010.
Nabeyama A, Kurita A, Asano K, Miyake Y, Yasuda T, Miura I, Nishitai G, Arakawa S, Shimizu S, Wakana S, Yoshida H, Tanaka M. xCT deficiency accelerates chemically induced tumorigenesis. Proc Natl Acad Sci U S A, 107: 6436-6441, 2010.
2009
Tomura M, Mori YS, Watanabe R, Tanaka M, Miyawaki A, Kanagawa O. Time-lapse observation of cellular function with fluorescent probe reveals novel CTL-target cell interactions. Int Immunol, 21: 1145-1150, 2009.
Qiu CH, Miyake Y, Kaise H, Kitamura H, Ohara O, Tanaka M. Novel subset of CD8{alpha}+ dendritic cells localized in the marginal zone is responsible for tolerance to cell-associated antigens. J Immunol, 182: 4127-4136, 2009.
2008
Tanaka M, Miyake Y, Asano K. Maintenance of self-tolerance by apoptotic cell clearance. Front Biosci, 13: 6043-6049, 2008.
2007
Witasp E, Uthaisang W, Elenstrom-Magnusson C, Hanayama R, Tanaka M, Nagata S, Orrenius S, Fadeel B. Bridge over troubled water: milk fat globule epidermal growth factor 8 promotes human monocyte-derived macrophage clearance of non-blebbing phosphatidylserine-positive target cells. Cell Death Differ, 14: 1063-1065, 2007.
Tanaka M,Miyake Y. Apoptotic cell clearance and autoimmune disorder. Curr Med Chem, 14: 2892-2897, 2007.
Miyake Y, Kaise H, Isono K, Koseki H, Kohno K, Tanaka M. Protective Role of Macrophages in Noninflammatory Lung Injury Caused by Selective Ablation of Alveolar Epithelial Type II Cells. J Immunol, 178: 5001-5009, 2007.
Miyake Y, Asano K, Kaise H, Uemura M, Nakayama M, Tanaka M. Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. J Clin Invest 117: 2268-2278, 2007.
Hijikata A, Kitamura H, Kimura Y, Yokoyama R, Aiba Y, Bao Y, Fujita S, Hase K, Hori S, Ishii Y, Kanagawa O, Kawamoto H, Kawano K, Koseki H, Kubo M, Kurita-Miki A, Kurosaki T, Masuda K, Nakata M, Oboki K, Ohno H, Okamoto M, Okayama Y, J OW, Saito H, Saito T, Sakuma M, Sato K, Sato K, Seino K, Setoguchi R, Tamura Y, Tanaka M, Taniguchi M, Taniuchi I, Teng A, Watanabe T, Watarai H, Yamasaki S, Ohara O. Construction of an open-access database that integrates cross-reference information from the transcriptome and proteome of immune cells. Bioinformatics, 23: 2934-2941, 2007.
2006
Nakaya M, Tanaka M, Okabe Y, Hanayama R, Nagata S. Opposite effects of rho family GTPases on engulfment of apoptotic cells by macrophages. J Biol Chem, 281: 8836-8842, 2006.
2005
Tanaka M. Apoptotic cell clearance by phagocytes. International Congress Series 1285, 55-59, 2005.
2004
Miyasaka K, Hanayama R, Tanaka M, Nagata S. Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur J Immunol, 34: 1414-1422, 2004.
Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S. Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice. Science, 304: 1147-1150, 2004.
Hanayama R, Tanaka M, Miwa K, Nagata S. Expression of Developmental Endothelial Locus-1 in a Subset of Macrophages for Engulfment of Apoptotic Cells. J Immunol, 172: 3876-3882, 2004.
Asano K, Miwa M, Miwa K, Hanayama R, Nagase H, Nagata S, Tanaka M. Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med, 200: 459-467, 2004.
2003
Tada K, Tanaka M, Hanayama R, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Tethering of Apoptotic Cells to Phagocytes through Binding of CD47 to Src Homology 2 Domain-Bearing Protein Tyrosine Phosphatase Substrate-1. J Immunol, 171: 5718-5726, 2003.
Nagase H, Fukuyama H, Tanaka M, Kawane K, Nagata S. Mutually regulated expression of caspase-activated DNase and its inhibitor for apoptotic DNA fragmentation. Cell Death Differ, 10: 142-143, 2003.
2002
Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Identification of a factor that links apoptotic cells to phagocytes. Nature, 417: 182-187, 2002.
2001
Shudo K, Kinoshita K, Imamura R, Fan H, Hasumoto K, Tanaka M, Nagata S, Suda T. The membrane-bound but not the soluble form of human Fas ligand is responsible for its inflammatory activity. Eur J Immunol, 31: 2504-2511, 2001.
Itai T, Tanaka M, Nagata S. Processing of tumor necrosis factor by the membrane-bound TNF-alpha- converting enzyme, but not its truncated soluble form. Eur J Biochem, 268: 2074-2082., 2001.
2000
McIlroy D, Tanaka M, Sakahira H, Fukuyama H, Suzuki M, Yamamura K, Ohsawa Y, Uchiyama Y, Nagata S. An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes. Genes Dev, 14: 549-558, 2000.
1999
Tanaka M, Fuentes ME, Yamaguchi K, Durnin MH, Dalrymple SA, Hardy KL, Goeddel DV. Embryonic lethality, liver degeneration, and impaired NF-kappaB activation in IKK-beta-deficient mice. Immunity, 10: 421-429, 1999.
Cao Z, Tanaka M, Regnier C, Rothe M, Yamit-hezi A, Woronicz JD, Fuentes ME, Durnin MH, Dalrymple SA, Goeddel DV. NF-kappa B activation by tumor necrosis factor and interleukin-1. Cold Spring Harb Symp Quant Biol, 64: 473-483, 1999.
1998
Yagi T, Sugimoto A, Tanaka M, Nagata S, Yasuda S, Yagita H, Kuriyama T, Takemori T, Tsunetsugu-Yokota Y. Fas/FasL interaction is not involved in apoptosis of activated CD4+ T cells upon HIV-1 infection in vitro. J Acquir Immune Defic Syndr Hum Retrovirol, 18: 307-315, 1998.
Toyozaki T, Hiroe M, Tanaka M, Nagata S, Ohwada H, Marumo F. Levels of soluble Fas ligand in myocarditis. Am J Cardiol, 82: 246-248, 1998.
Tanaka M, Itai T, Adachi M, Nagata S. Downregulation of Fas ligand by shedding. Nat Med, 4: 31-36, 1998.
Mizuki M, Ueda S, Tagawa S, Shibayama H, Nishimori Y, Shibano M, Asada H, Tanaka M, Nagata S, Koudera U, Suzuki K, Machii T, Ohsawa M, Aozasa K, Kitani T, Kanakura Y. Natural killer cell-derived large granular lymphocyte lymphoma of lung developed in a patient with hypersensitivity to mosquito bites and reactivated Epstein-Barr virus infection. Am J Hematol, 59: 309-315, 1998.
Hashimoto H, Tanaka M, Suda T, Tomita T, Hayashida K, Takeuchi E, Kaneko M, Takano H, Nagata S, Ochi T. Soluble Fas ligand in the joints of patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum, 41: 657-662, 1998.
Adachi S, Ito H, Tamamori M, Tanaka M, Marumo F, Hiroe M. Skeletal and smooth muscle alpha-actin mRNA in endomyocardial biopsy samples of dilated cardiomyopathy patients. Life Sci, 63: 1779-1791, 1998.
1997
Tanaka M, Suda T, Yatomi T, Nakamura N, Nagata S. Lethal effect of recombinant human Fas ligand in mice pretreated with Propionibacterium acnes. J Immunol, 158: 2303-2309, 1997.
Suda T, Hashimoto H, Tanaka M, Ochi T, Nagata S. Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing. J Exp Med, 186: 2045-2050, 1997.
Ertel W, Keel M, Stocker R, Imhof HG, Leist M, Steckholzer U, Tanaka M, Trentz O, Nagata S. Detectable concentrations of Fas ligand in cerebrospinal fluid after severe head injury. J Neuroimmunol, 80: 93-96, 1997.
Bahr GM, Capron A, Dewulf J, Nagata S, Tanaka M, Bourez JM, Mouton Y. Elevated serum level of Fas ligand correlates with the asymptomatic stage of human immunodeficiency virus infection. Blood, 90: 896-898, 1997.
1996
Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, Motoyoshi K, Mizuki M, Tagawa S, Ohga S, Hatake K, Drummond AH, Nagata S. Fas ligand in human serum. Nat Med, 2: 317-322, 1996.
Takeda K, Yu ZX, Nishikawa T, Tanaka M, Hosoda S, Ferrans VJ, Kasajima T. Apoptosis and DNA fragmentation in the bulbus cordis of the developing rat heart. J Mol Cell Cardiol, 28: 209-215, 1996.
Takahashi T, Tanaka M, Ogasawara J, Suda T, Murakami H, Nagata S. Swapping between Fas and granulocyte colony-stimulating factor receptor. J Biol Chem, 271: 17555-17560, 1996.
Suda T, Tanaka M, Miwa K, Nagata S. Apoptosis of mouse naive T cells induced by recombinant soluble Fas ligand and activation-induced resistance to Fas ligand. J Immunol, 157: 3918-3924, 1996.
Sato K, Kimura F, Nakamura Y, Murakami H, Yoshida M, Tanaka M, Nagata S, Kanatani Y, Wakimoto N, Nagata N, Motoyoshi K. An aggressive nasal lymphoma accompanied by high levels of soluble Fas ligand. Br J Haematol, 94: 379-382, 1996.
Ito H, Adachi S, Tamamori M, Fujisaki H, Tanaka M, Lin M, Akimoto H, Marumo F, Hiroe M. Mild hypoxia induces hypertrophy of cultured neonatal rat cardiomyocytes: a possible endogenous endothelin-1-mediated mechanism. J Mol Cell Cardiol, 28: 1271-1277, 1996.
Estaquier J, Tanaka M, Suda T, Nagata S, Golstein P, Ameisen JC. Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists. Blood, 87: 4959-4966, 1996.
Akimoto H, Ito H, Tanaka M, Adachi S, Hata M, Lin M, Fujisaki H, Marumo F, Hiroe M. Heparin and heparan sulfate block angiotensin II-induced hypertrophy in cultured neonatal rat cardiomyocytes. A possible role of intrinsic heparin-like molecules in regulation of cardiomyocyte hypertrophy. Circulation, 93: 810-816, 1996.
1995
Tanaka M, Suda T, Takahashi T, Nagata S. Expression of the functional soluble form of human fas ligand in activated lymphocytes. Embo J, 14: 1129-1135, 1995.
Tanaka M, Hiroe M, Ito H, Nishikawa T, Adachi S, Aonuma K, Marumo F. Differential localization of atrial natriuretic peptide and skeletal alpha-actin messenger RNAs in left ventricular myocytes of patients with dilated cardiomyopathy. J Am Coll Cardiol, 26: 85-92, 1995.
Fujisaki H, Ito H, Hirata Y, Tanaka M, Hata M, Lin M, Adachi S, Akimoto H, Marumo F, Hiroe M. Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. J Clin Invest, 96: 1059-1065, 1995.
Adachi S, Ito H, Ohta Y, Tanaka M, Ishiyama S, Nagata M, Toyozaki T, Hirata Y, Marumo F, Hiroe M. Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial banding. Am J Physiol, 268: H162-169, 1995.
1994
Tanaka M, Ito H, Adachi S, Akimoto H, Nishikawa T, Kasajima T, Marumo F, Hiroe M. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res, 75: 426-433, 1994.
Tanaka M, Hiroe M, Nishikawa T, Sato T, Marumo F. Cellular localization and structural characterization of natriuretic peptide-expressing ventricular myocytes from patients with dilated cardiomyopathy. J Histochem Cytochem, 42: 1207-1214, 1994.
Takahashi T, Tanaka M, Inazawa J, Abe T, Suda T, Nagata S. Human Fas ligand: gene structure, chromosomal location and species specificity. Int Immunol, 6: 1567-1574, 1994.
Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell, 76: 969-976, 1994.
Adachi S, Ito H, Akimoto H, Tanaka M, Fujisaki H, Marumo F, Hiroe M. Insulin-like growth factor-II induces hypertrophy with increased expression of muscle specific genes in cultured rat cardiomyocytes. J Mol Cell Cardiol, 26: 789-795, 1994.
1993
Kawai M, Nishikawa T, Tanaka M, Ando A, Kasajima T, Higa T, Tanikawa T, Kagawa M, Momma K. An autopsied case of Williams syndrome complicated by moyamoya disease. Acta Paediatr Jpn, 35: 63-67, 1993.
Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Murumo F, Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest, 92: 398-403, 1993.
著書
Tanaka M, Nishitai G. Immune Regulation by Dead Cell Clearance. Curr Top Microbiol Immunol 403; 171-83, 2017.
Nagata S, Tanaka M. Programmed cell death and the immune system. Nat Rev Immunol 17; 333-40, 2017.
Kenichi Asano and Masato Tanaka‘Development of Sentinel-Cell Targeted Therapy for Inflammatory Bowel Diseases’Chronic Inflammation, Chapter 46, pp.617-626 DOI: 10.1007/978-4-431-56068-5_46
Nagata S, Tanaka M. Programmed cell death and the immune system. Nat Rev Immunol. 2017 May;17(5):333-340. doi: 10.1038/nri.2016.153. Epub 2017 Feb 6. Review.
邦文総説
浅野 謙一、田中 正人「死細胞貪食マクロファージ」 実験医学増刊Vol.34-No.7 2016, pp.1089-1094
西躰 元, 田中 正人「死細胞貪食マクロファージ」臨床免疫・アレルギー科 63:431-435(2015)
浅野 謙一、唐澤 一徳、田中 正人「CD169発現常在マクロファージによる組織恒常性維持と免疫制御」細胞工学 33:1261-1266(2014)
浅野 謙一、田中 正人「CD169陽性マクロファージの免疫制御機能」感染・炎症・免疫 41:26-34(2011)
浅野 謙一、田中 正人「死細胞の貪食異常と自己免疫疾患」実験医学26: 3019-3024(2008)
浅野 謙一、田中 正人「食細胞によるアポトーシス細胞の貪食異常と、自己免疫疾患」Molecular Medicine 41: 171-177(2005)
Publication List 准教授 浅野 謙一
2018
Kikuchi K, Iida M, Ikeda N, Moriyama S, Hamada M, Takahashi S, Kitamura H, Watanabe T, Hasegawa Y, Hase K, Fukuhara T, Sato H, Kobayashi EH, Suzuki T, Yamamoto M, Tanaka M, Asano K. Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation. J Immunol 201; 635-51, 2018.
Ikeda N, Asano K, Kikuchi K, Uchida Y, Ikegami H, Takagi R, Yotsumoto S, Shibuya T, Makino-Okamura C, Fukuyama H, Watanabe T, Ohmuraya M, Araki K, Nishitai G, Tanaka M. Emergence of immunoregulatory Ym1(+)Ly6C(hi) monocytes during recovery phase of tissue injury. Sci Immunol 3; 2018.
Deguchi Y, Nishina T, Asano K, Ohmuraya M, Nakagawa Y, Nakagata N, Sakuma T, Yamamoto T, Araki K, Mikami T, Tanaka M, Nakano H. Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice. Biochem Biophys Res Commun 505; 453-9, 2018.
2017
Itoh M, Suganami T, Kato H, Kanai S, Shirakawa I, Sakai T, Goto T, Asakawa M, Hidaka I, Sakugawa H, Ohnishi K, Komohara Y, Asano K, Sakaida I, Tanaka M, Ogawa Y. CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis. JCI Insight 2; 2017.
Arai Y, Takahashi D, Asano K, Tanaka M, Oda M, Ko SBH, Ko MSH, Mandai S, Nomura N, Rai T, Uchida S, Sohara E. Salt suppresses IFNgamma inducible chemokines through the IFNgamma-JAK1-STAT1 signaling pathway in proximal tubular cells. Sci Rep 7; 46580, 2017.
2016
Matsushita N, Suzuki M, Ikebe E, Nagashima S, Inatome R, Asano K, Tanaka M, Matsushita M, Kondo E, Iha H, Yanagi S.‘Regulation of B cell differentiation by the ubiquitin-binding protein TAX1BP1.’Scientific Reports. 2016 Aug 12;6:31266. doi: 10.1038/srep31266.
2015
Motomura Y, Kanno S, Asano K, Tanaka M, Hasegawa Y, Katagiri H, Saito T, Hara H, Nishio H, Hara T, Yamasaki S. ‘Identification of Pathogenic Cardiac CD11c+ Macrophages in Nod1-Mediated Acute Coronary Arteritis.’ Arterioscler Thromb Vasc Biol. 35(6):1423-33, 2015. doi: 10.1161/ATVBAHA.114.304846
Inoue H, Matsuzaki Y, Tanaka A, Hosoi K, Ichimura K, Arasaki K, Wakana Y, Asano K, Tanaka M, Okuzaki D, Yamamoto A, Tani K, Tagaya M. ‘γ-SNAP stimulates disassembly of endosomal SNARE complexes and regulates endocytic trafficking pathways.’ J Cell Sci. 128(15):2781-94, 2015. doi: 10.1242/jcs.158634.
Asano K, Takahashi N, Ushiki M, Monya M, Aihara F, Kuboki E, Moriyama S, Iida M, Kitamura H, Qiu CH, Watanabe T, Tanaka M. ‘Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes.’ Nat Commun. 21;6:7802, 2015.doi: 10.1038/ncomms8802.
Karasawa K., Asano K., Moriyama S., Ushiki M., Monya M., Iida M., Kuboki E., Yagita H., Uchida K., Nitta K., and Tanaka M.‘Vascular-resident CD169-Positive Monocytes and macrophages Control Neutrophil Accumulation in the Kidney with Ischemia-reperfusion Injury’Journal of American Society of Nephrology 26:896-906 (2015)
2014
Taguchi K., Okada A., Kitamura H., Yasui T., Naiki T., Hamamoto S., Ando R., Mizuno K., Kawai N., Tozawa K., Asano K., Tanaka M., Miyoshi I., and Kohri K.‘Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation’Journal of American Society of Nephrology 25:1680-1697 (2014)
2011
Asano K., Nabeyama A., Miyake Y., Qiu C.H., Kurita A., Tomura M., Kanagawa O., Fujii S., Tanaka M.‘CD169-Positive Macrophages Dominate Antitumor Immunity by Crosspresenting Dead Cell-Associated Antigens.’Immunity 34: 85-95 (2011).
2010
Tanaka M, Asano K, Qiu CH.‘Immune regulation by apoptotic cell clearance.’Annals of New York Academy of Sciences 1209: 37-42 (2010).
Nabeyama A., Kurita A., Asano K., Miyake Y., Yasuda T., Miura I., Nishitai G., Arakawa S., Shimizu S., Wakana S., Yoshida H., Tanaka M.‘xCT deficiency accelerates chemically induced tumorigenesis.’Proceedings of the National Academy of Sciences of the United States of America 107:6436-6441 (2010).
2009
Okamoto Y., Christen T., Shimizu K., Asano K., Kihara S., Mitchell RN, Libby P.‘Adiponectin inhibits allograft rejection in murine cardiac transplantation.’Transplantation 88: 879-883 (2009).
2008
Tsuboi N*., Asano K.*, Lauterbach M., Mayadas TN. (* Equally contributed）‘Human neutrophil Fc receptors initiate and play selective roles in antibody- mediated inflammatory diseases.’Immunity 28: 833- 846 (2008).
Tanaka M., Miyake Y., Asano, K.‘Maintenance of self- tolerance by apoptotic cell clearance.’Frontiers in Bioscience 13: 6043- 6049 (2008).
Utomo A., Hirahashi J., Mekala D., Asano, K., Glogauer M., Cullere X., Mayadas TN.‘Requirement for Vav proteins in post-recruitment neutrophil cytotoxicity in IgG but not complement C3- dependent injury.’Journal of Immunology 180: 6279- 6287 (2008).
Shimizu K., Libby P., Shubiki R., Sakuma M., Wang Y., Asano K., Mitchell RN., Simon DI.‘Leukocyte integrin Mac-1 promotes acute cardiac allograft rejection.’Circulation 117: 1997-2008 (2008).
Lauterbach M., O’Donnel P., Asano, K., Mayadas TN.‘Role of TNF priming and adhesion molecules in neutrophil recruitment to intravascular immune complexes.’Journal of Leukocyte Biology 83: 1423- 1430 (2008).
2007
Miyake Y.*, Asano K.*, Kaise H., Uemura M., Nakayama M., Tanaka M. (*Equallycontributed）‘Critical role of macrophages in the marginal zone in immune suppression to apoptotic cell-associated antigens.’The Journal of Clinical Investigation 117: 2268- 2278 (2007).
2004
Asano K. Miwa M., Miwa K., Hanayama R., Nagase H., Nagata S., Tanaka, M.‘Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice.’ Journal of Experimental Medicine 200: 459- 467 (2004).
著書
Kenichi Asano and Masato Tanaka‘Development of Sentinel-Cell Targeted Therapy for Inflammatory Bowel Diseases’Chronic Inflammation, Chapter 46, pp.617-626 DOI: 10.1007/978-4-431-56068-5_46
邦文総説
浅野 謙一、田中 正人「死細胞貪食マクロファージ」 実験医学増刊Vol.34-No.7 2016, pp.1089-1094
浅野 謙一、唐澤 一徳、田中 正人「CD169発現常在マクロファージによる組織恒常性維持と免疫制御」細胞工学 33:1261-1266(2014)
浅野 謙一、田中 正人「CD169陽性マクロファージの免疫制御機能」感染・炎症・免疫 41:26-34(2011)
浅野 謙一、田中 正人「死細胞の貪食異常と自己免疫疾患」実験医学26: 3019-3024(2008)
浅野 謙一、田中 正人「食細胞によるアポトーシス細胞の貪食異常と、自己免疫疾患」Molecular Medicine 41: 171-177(2005)
主要特許
「炎症性腸疾患を抑制する抗体および該抗体を含む医薬組成物」特願2015-106658
「抗原結合アポトーシス細胞を用いる免疫反応の制御」2006年(出願番号2006-286732)
Publication List 助教 四元 聡志
2018
Ikeda N, Asano K, Kikuchi K, Uchida Y, Ikegami H, Takagi R, Yotsumoto S, Shibuya T, Makino-Okamura C, Fukuyama H, Watanabe T, Ohmuraya M, Araki K, Nishitai G, Tanaka M. Emergence of immunoregulatory Ym1(+)Ly6C(hi) monocytes during recovery phase of tissue injury. Sci Immunol 3; 2018.
2017
Yotsumoto S, Muroi Y, Chiba T, Ohmura R, Yoneyama M, Magarisawa M, Dodo K, Terayama N, Sodeoka M, Aoyagi R, Arita M, Arakawa S, Shimizu S, Tanaka M. Hyperoxidation of ether-linked phospholipids accelerates neutrophil extracellular trap formation. Sci Rep 7; 16026, 2017.
Kawamura S, Onai N, Miya F, Sato T, Tsunoda T, Kurabayashi K, Yotsumoto S, Kuroda S, Takenaka K, Akashi K, Ohteki T.Identification of a Human Clonogenic Progenitor with Strict Monocyte Differentiation Potential: A Counterpart of Mouse cMoPs. Immunity. 2017 May 16;46(5):835-848.
2016以前
Ohyagi H, Onai N, Sato T, Yotsumoto S, Liu J, Akiba H, Yagita H, Atarashi K, Honda K, Roers A, Müller W, Kurabayashi K, Hosoi-Amaike M., Takahashi N., Hirokawa M., Matsushima K., Sawada K. & Ohteki T. Monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses. Immunity 39, p584-598. (2013).
Sato T., Ikeda M., Yotsumoto S., Shimada Y., Higuchi T., Kobayashi H., Fukuda T., Ohashi T., Suda T. & Ohteki T. Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. Blood 121, p3267-3273. (2013).
Yotsumoto S., Saegusa K. & Aramaki Y. Endosomal translocation of CpG-oligodeoxynucleotides inhibits DNA-PKcs-dependent IL-10 production in macrophages. J Immunol 180, p809-816 (2008).
Saegusa K, Yotsumoto S., Kato S. & Aramaki Y. Phosphatidylinositol 3-kinase-mediated regulation of IL-10 and IL-12 production in macrophages stimulated with CpG oligodeoxynucleotide. Mol Immunol 44, p1323-1330. (2007).
Yotsumoto S., Kakiuchi T. & Aramaki Y. Enhancement of IFN-gamma production for Th1-cell therapy using negatively charged liposomes containing phosphatidylserine. Vaccine 25, p5256-5262. (2007).
Inoue J., Yotsumoto S., Sakamoto T., Tsuchiya S. & Aramaki Y. Changes in immune responses to mite antigen sensitized through barrier-disrupted skin with CpG-oligodeoxynucleotide in mice. Biol Pharm Bull 29, p385-387 (2006).
Yoshida T., Oide N., Sakamoto T., Yotsumoto S., Negishi Y., Tsuchiya S. & Aramaki Y. Induction of cancer cell-specific apoptosis by folate-labeled cationic liposomes. J Control Release 111, p325-332. (2006).
Inoue J., Yotsumoto S., Sakamoto T., Tsuchiya S. & Aramaki Y. Changes in immune responses to antigen applied to tape-stripped skin with CpG-oligodeoxynucleotide in mice. J Control Release 108, p294-305. (2005).
Inoue J., otsumoto S., Sakamoto T., Tsuchiya S. & Aramaki Y. Changes in immune responses to antigen applied to tape-stripped skin with CpG-oligodeoxynucleotide in NC/Nga mice. Pharm Res 22, p1627-1633. (2005).
Yotsumoto S., Kakiuchi T. & Aramaki Y. Negatively charged phospholipids suppress IFN-gamma production in T cells. Biochem Biophys Res Commun 338, p1719-1725. (2005).
Yotsumoto S., Aramaki Y., Kakiuchi T. & Tsuchiya S. Induction of antigen-dependent interleukin-12 production by negatively charged liposomes encapsulating antigens. Vaccine 22, 3503-3509. (2004).
Aramaki Y., Yotsumoto S., Watanabe H. & Tsuchiya S. NADPH-oxidase may contribute to IL-12 production in macrophages stimulated with CpG phosphorothioate oligodeoxynucleotides. Biol Pharm Bull 25, p351-355. (2002).
総説・著書
四元聡志, 田中正人. 好中球細胞外トラップの誘導機構とその生理的および病理的意義. 臨床免疫・アレルギー科. 70巻3号p301. (2018)
四元聡志, 樗木俊聡. IL-15. 朝倉書店, 桂義元, 河本 宏, 小安重夫, 山村一彦 (編) 免疫の事典. p61. (2011).
横山 晴子, 四元 聡志, 坂本 宜俊, 新槇幸彦, 山田安彦. カレントトピックス2005 注射剤調剤; 第1章 注射剤調剤の推進に向けて.月刊薬事 臨時増刊. 47巻4号p549. (2005).