発表論文

　

2007

1. Koichiro Takahashi, Takuma Shibata, Sachiko Akashi-Takamura, Takashi Kiyokawa, Yasutaka Wakabayashi, Natsuko Tanimura, Toshihiko Kobayashi, Fumi Matsumoto, Ryutaro Fukui, Taku Kouro, Yoshinori Nagai, Kiyoshi Takatsu, Shin-ichiroh Saitoh, and Kensuke Miyake. A protein associated with Toll-like receptor(TLR)4(PRAT4A) is required for TLR-dependent immune responses. J.Exp.Med. 204: 2963-2976, 2007.

概要：われわれはPRAT4Aのノックアウトマウスを作製した。その結果、１．PRAT4AはTLR4のみならずTLR1,TLR9など他のTLRともERで会合しており、これらTLRのERからのトラフィッキングにはPRAT4Aが必要であること、２．PRAT4AノックアウトマウスではTLR3には影響ないがTLR7,9などの細胞内TLR応答は消失し、TLR1,2,4などの細胞表面TLR応答は部分的に残っている、というように個々のTLRによってPRAT4A依存性が異なることから、PRAT4AはTLR相互の免疫応答バランスを調整していることが考えられること、３．PRAT4Aノックアウトマウスはエンドトキシンショックに抵抗性であることから、エンドトキシンショック誘導にはPRAT4A依存的な経路が必要であること、などが明らかとなった。今後PRAT4Aがエンドトキシンショック治療の新たなターゲットとなる可能性も示唆される。


2. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler. Thomb. Vasc. Biol. 2007, 27: 84-91.

2. Miyake K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol. 2007, 19: 3-10.

4. Ohto U, Fukase K, Miyake K, Satow Y. Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 2007, 316:1632-1634.

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2006

1. Yasutaka Wakabayashi, Makiko Kobayashi, Sachiko Akashi-Takamura,Natsuko Tanimura,Kazunori Konno,Koichiro Takahashi, Takashi Ishii, Taketoshi Mizutani, Hideo Iba, Taku Kouro,Satoshi Takaki, Kiyoshi Takatsu, Yoshiya Oda, Yasushi Ishihama, Shin-ichiroh Saitoh, and Kensuke Miyake.A Protein Associated with Toll-like Receptor 4 (PRAT4A) Regulates Cell Surface Expression of TLR41.Journal of Immunology 2006,177:1772-1779.

概要：あらたにみつけたTLR4会合分子、PRAT4AはTLR4のimmature formに会合する40kDの分子である。RNAiによりこの分子の発現を抑制するとTLR4/MD-2の細胞表面での発現が消失しさらにLPS刺激によるNF-ｋBの活性化も見られなくなることから、PRAT4AはTLR4/MD-2の細胞表面への発現を調節している分子であることがわかった。


2.Akashi-Takamura S, Furuta T, Takahashi K, Tanimura N, Kusumoto Y, Kobayashi T, Saitoh S, Adachi Y, Doi T, Miyake K. Agonistic Antibody to TLR4/MD-2 Protects Mice from Acute Lethal Hepatitis Induced by TNF-{alpha}. Journal of Immunology 2006 Apr 1;176(7):4244-51.

概要：作製したTLR4/MD-2に対するモノクローナル抗体のうち、LPS+D-galactosamineによるマウスエンドトキシンショックを抑制するのはLPS刺激抑制抗体ではなくむしろ刺激を増強させる活性化抗体であった。この抗体による抑制効果はTLR4ミュータントマウスではほとんど認められず、TLR4/MD-2を介してアポトーシスを抑制するシグナルを入れている可能性が考えられた。マイクロアレイやRT-PCR,　Northernなどの結果からこの抗体を投与したマウスの肝臓では特異的に抗アポトーシス遺伝子発現上昇が見られ、積極的にこれらの遺伝子発現を誘導していると考えられた。


3.Okamoto M, Oshikawa T, Tano T, Ahmed SU, Kan S, Sasai A, Akashi S, Miyake K, Moriya Y, Ryoma Y, Saito M, Sato M. Mechanism of Anticancer Host Response Induced by OK-432, a Streptococcal Preparation, Mediated by Phagocytosis and Toll-Like Receptor 4 Signaling. J Immunother.;29(1):78-86. 2006.

4.Konno K, Wakabayashi Y, Akashi-Takamura S, Ishii T, Kobayashi M, Takahashi K, Kusumoto Y, Saitoh S, Yoshizawa Y, Miyake K. 2006. A molecule that is associated with Toll-like receptor 4 and regurates its cell surface expression. Biochem Biophys Res Commun. 339(4):1076-1082.

概要：われわれはTLR4のimmature formに会合する分子の同定に成功し, これらの分子を各々PRAT4(PRotein Associated with TLR4)A,　およびPRAT4Bと命名した。どちらも交差することなく独立してTLR4のimmature formに会合し、MD-2とは別にTLR4の細胞表面への発現を調節している分子であることがわかった。


5.Kobayashi M, Saitoh S, Tanimura N, Takahashi K, Kawasaki K, Nishijima M, Fujimoto Y, Fukase K, Akashi-Takamura S, Miyake K: Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. J Immunol. 2006, 176:6211-6218.

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2005

1.Nagai Y, Kobayashi T, Motoi Y, Ishiguro K, Akashi S, Saitoh S, Kusumoto Y, Kaisho T, Akira S, Matsumoto M, Takatsu K, Miyake K. 2005. The Radioprotective 105/MD-1 Complex Links TLR2 and TLR4/MD-2 in Antibody Response to Microbial Membranes. J. Immunol. 174(11):7043-7049.

概要：B細胞表面に発現するRP105/MD-1が、TLR2･TLR4リガンドに代表される細菌表層成分によって誘導される抗体産生を正に制御していることをRP105 KOマウスを用いて明らかにした。RP105の欠損によりB細胞のリポペプチドやLPSへの増殖応答性の低下とプラズマ細胞への分化が阻害される結果、抗体産生の誘導が低下することを明らかにした。


2.Nagaoka K, Takahara K, Tanaka K, Yoshida H, Steinman RM, Saitoh S, Akashi-Takamura S, Miyake K, Kang YS, Park CG, Inaba K. Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria. Int Immunol. 2005 Jul;17(7):827-36.

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2004

1.Shin-ichiroh Saitoh, Sachiko Akashi, Takenao Yamada, Natsuko Tanimura, Makiko Kobayashi, Kazunori Konno, Fumi Matsumoto, Koichi Fukase, Shoichi, Kusumoto, Yoshinori Nagai, Yutaka Kusumoto, Atsushi Kosugi, and Kensuke Miyake. 2004. Lipid A Antagonist, Lipid IVa, Is Distinct from Lipid A in Interaction with Toll-like receptor 4 (TLR4)-MD-2 and Ligand-induced TLR4-oligomerization. Int Immunol. 16(7):961-969.

概要：TLR4はLPSを認識してからTLR4同士の多量体を形成することをはじめて生化学的に明 らかにした。このTLR4の多量体の形成がシグナル伝達を開始する上で重要な役割を果たしており、そのアンタゴニストはTLR4に結合するものの多量体を形成させないことで作用していることを明らかにした。


2.Saitoh S, Akashi S, Yamada T, Tanimura N, Matsumoto F, Fukase K, Kusumoto S, Kosugi A, Miyake K. Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling.　J Endotoxin Res. 2004. 10(4):257-60.

3. Iwahashi M, Yamamura M, Aita T, Okamoto A, Ueno A, Ogawa N, Akashi S, Miyake K, Godowski PJ, Makino H. Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis.Arthritis Rheum. 2004. 50(5):1457-67.

4. Okamoto M, Oh-EG, Oshikawa T, Furuichi S, Tano T, Ahmed SU, Akashi S, Miyake K, takeuchi O, Akira S, Himeno K, Sato M, Ohkubo S. Toll-like receptor 4 mediates the antitumor host response induced by a 55-kilodalton protein isolated from Aeginetia indica L., a parasitic plant.　Clin Diagn Lab Immunol. 2004. 11(3):483-95.

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2003

1. Akashi, S., S. Saitoh, Y. Wakabayashi, T. Kikuchi, N. Takamura, Y. Nagai, Y. Kusumoto, K. Fukase, S. Kusumoto, Y. Adachi, A. Kosugi, and K. Miyake. 2003. Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4-MD-2 Higher Affinity than that with MD-2 or CD14. J. Exp. Med. 198: 1035-1042.

概要：あらたに作製したTLR4/MD-2に対するモノクローナル抗体を用いてLPSとTLR4/MD-2との細胞レベルでの直接結合を証明することに成功し、この解析系を用いてLPS拮抗剤がCD14よりむしろTLR4/MD-2へ作用していることを明らかにした。


2. Okamoto M，Oshikawa T, Tano T, Ohe G, Furuichi S, Nishikawa H, Ahmed SU, Akashi S, Miyake K, Takeuchi O, Akira S, Moriya Y, Matsubara S, Ryoma Y, Saito M, Sato M. 2003. Involvement of Toll-like receptor 4 signaling in interferon-gamma production and antitumor effect by streptococcal agent OK-432. J Natl Cancer Inst. 19;95(4):316-26.

3.Dory D, Echchannaoui H, Letiembre M, Ferracin F, Pieters J, Adachi Y, Akashi S, Zimmerli W, Landmann R.　2003. Generation and functional characterization of a clonal murine periportal Kupffer cell line from H-2Kb -tsA58 mice. J Leukoc Biol. Jul;74(1):49-59.

4.Hatakeyama J, Tamai R, Sugiyama A, Akashi S, Sugawara S, Takada H.　2003. Contrasting responses of human gingival and periodontal ligament fibroblasts to bacterial cell-surface components through the CD14/Toll-like receptor system. Oral Microbiol Immunol. Feb;18(1):14-23.

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2002

1. Nagai, Y., S. Akashi, M. Nagafuku, M. Ogata, Y. Iwakura, S. Akira, T. Kitamura, A. Kosugi, M. Kimoto, and K. Miyake. 2002. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat.immunol. 3:667-672

2. Nagai, Y., R. Shimazu, H. Ogata, S. Akashi, K. Sudo, H. Yamasaki, S. -I. Hayashi, Y. Iwakura, M. Kimoto, and K. Miyake. 2002. Requirement for MD-1 in Cell Surface Expression of RP105/CD180 and B Cell Responsiveness to Lipopolysaccharide. Blood. 99:1699-1705.

3. Miyake K, Nagai Y, Akashi S, Nagafuku M, Ogata M, Kosugi A. 2002. Essential role of MD-2 in B-cell responses to lipopolysaccharide and Toll-like receptor 4 distribution. J Endotoxin Res. 8(6):449-52.

4. Hijiya, N., Miyake, K., Akashi,S., Matsuura, K., Higuchi, Y., Yamamoto, S. 2002. Possible Involvement of Toll-Like Rreceptor 4 in Endotherial cell Activation of Larger Vessels in Response to Lipopolysaccharide. Pathobiolog,70:18-25.

5. Tada H, Nemoto E, Shimauchi H, Watanabe T, Mikami T, Matsumoto T, Ohno N, Tamura H, Shibata K, Akashi S, Miyake K, Sugawara S, Takada H. 2002. Saccharomyces cerevisiae-and Candida albicans Derived Mannan Induced Production of Tumor Necrosis Factor Alpha by Human Monocytes in a CD14-and Toll-like Receptor4-Dependent Manner. Mcrobiol.Immunol.,46(7),503-512,

6. Ishida I, Kubo H, Suzuki S, Suzuki T, Akashi S, Inoue K, Maeda S, Kikuchi H, Sasaki H, Kondo T. 2002. Hypoxia diminishes toll-like receptor 4 expression through reactive oxygen species generated by mitochondria in endothelial cells. J Immunol. 15;169(4):2069-75.

7. Kitamura K, Kanehira K, Shiina T, Morimatsu M, B.D.Jung, Akashi S, Saito M. 2002. Bacterial Lipopolysaccharide Induces mRNA Expression of an IkB MAIL through Toll-Like Receptor4.,J.Vet.Med.Sci.64(5): 419-422,

8. Tamai R, Sakuta T, Matsushita K, Torii M, Takeuchi O, Akira S, Akashi S, Espevik T, Sugawara S, Takeda H. 2002. Human gingival CD14(+) fibroblasts primed with gamma interferon increase production of interleukin-8 in response to lipopolysaccharide through up-regulation of membrane CD14 and MyD88 mRNA expression. Infect Immun.70(3):1272-8.

9.Ando I, Tsukumo Y, Wakabayashi T, Akashi S, Miyake K, Kataoka T, Nagai K. 2002. Safflower polysaccharides activate the transcription factor NF-kappa B via Toll-like receptor 4 and induce cytokine production by macrophages. Int Immunopharmacol. Jul;2(8):1155-62.

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2001

1. Akashi, S., Y. Nagai, H. Ogata, M. Oikawa, K. Fukase, S. Kusumoto, K. Kawasaki, M. Nishijima, S. Hayashi, M. Kimoto, and K. Miyake. 2001. Human MD-2 Confers on Mouse Toll-like Receptor 4 Species-specific LPS Recognition. Int. Immunol. 13:1595-1599

2. Schromm, A. B., E. Lien, P. Henneke, J. C. Chow, A. Yoshimura, H. Heine, E. Latz, B. G. Monks, D. A. Schwartz, K. Miyake, and D. T. Golenbock. 2001. Moleculear genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J. Exp. Med. 194: 79-88.

3. Watanabe, Y., M. Hashizume, S. Kataoka, E. Hamaguchi, N. Mirimoto, S. Tsuru, S. Katoh, K. Miyake, K. Matsuhima, M. Tominaga, T. Kurashige, S. Fujimoto, P. W. Kincade, and A. Tominaga. 2001. Differentiation stages of eosinophils characterized by hyaluronic acid binding via CD44 and responsiveness to stimuli. DNA Cell Biol. 20: 189-202.

4. Sugawara S,Yang S, Iki K, Hatakeyama J, Tamai R, Takeuchi O, Akashi S, Espevik T, Akira S, Takada H. 2001. Monocytic cell activation by Nonendotoxic glycoprotein from Prevotella intermedia ATCC 25611 is mediated by toll-like receptor 2. Infect. Immunol. aug,69(8):4951-7.

5. Yang S, Tamai R, Akashi S, Takeuchi O, Akira S, Sugawara S, Takada H. 2001. Synergistic effect of muramyldipeptide with lipopolysaccharide or lipoteichoic acid to induce inflammatory cytokines in human monocytic cells in culture.Infect Immun. Apr;69(4):2045-53.

6. Yang, S., S. Sugawara, T. Monodane, M. Nishijima, Y. Adachi, S. Akashi, K. Miyake, S. Hase, and H. Takada. 2001. Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14-and Toll-Like Receptor4-Dependent Manner. Infect. Immun. 69: 2025-2030.

7. Kaji, K., S. Takeshita, K. Miyake, T. Takai, and A. Kudo. 2001. Functional association of CD9 with the Fcg receptors in macrophages. J. Immunol. 166: 3256-3265.

8. Dziarski, R., Q. Wang, K. Miyake, C. J. Kirschning, and D. Gupta. 2001. MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components. J. Immunol. 166: 1938-1944.

9. Lien, E., J. C. Chow, L. D. Hawkins, P. D. McGuiness, K. Miyake, T. Espevik, F. Gusovsky, and D. T. Golenbock. 2001. A novel synthetic acyclic lipid A-like agonist activates cells via the lipopolysaccharide/Toll-like receptor 4 signaling pathway. J. Biol. Chem. 276: 1873-1880.

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2000

1. M. Fukuoka, K. Fukudome, Y. Yamashita, M. Tokushima, K. Miyake, and M. Kimoto. 2000. Antiadhesive function of 130-kd glycoform of CD43 expressed in CD4 T-lymphocyte clones and transfectant cell lines. Blood 96: 4267-4275.

2. Tapping, R. I., S. Akashi, K. Miyake, P. J. Godowski, and P. S. Tobias. 2000. Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. J. Immunol. 165:5780-5787.

3. Thoma-Uszynski, S., S. M. Kiertsher, M. T. Ochoa, D. A. Bouis, M. V. Norgard, K. Miyake, P. Godowski, M. D. Roth, and R. L. Modlin. 2000. Activation of Toll-like receptor 2 on human dendritic cells triggers induction of IL-12, but not IL-10. J. Immunol. 165: 3804-3810.

4. Jiang, Q., S. Akashi, K. Miyake, and H. R. Petty. 2000. Cutting Edge: Lipopolysaccharide Induces Physical Proximity Between CD14 and Toll-Like Receptor 4 (TLR4) Prior to Nuclear Translocation of NF-kB. J. Immunol. 165: 3541-3544.

5. Sugawara, S., E. Nemoto, H. Tada, K. Miyake, T. Imamura, and H. Takada. 2000. Proteolysis of human monocyte CD14 by cysteine proteinases (gingipains) from Porphyromonas gingivalis leading to lipopolysaccharide hyporesponsiveness. J. Immunol. 165: 411-418.

6. Tabeta, K., K. Yamazaki, S. Akashi, K. Miyake, H. Kumada, T. Umemoto, and H. Yoshie. 2000. Toll-like receptors confer responsiveness to lipopolysaccharide from Porphyromonas gingivalis in human gingival fibroblasts. Infect. Immun. 68: 3731-3735.

7. Ogata, H., I. Su, K. Miyake, Y. Nagai, S. Akashi, I. Mecklenbrauker, K. Rajewsky, M. Kimoto, and A. Tarakhovsky. 2000. The Toll-like Receptor Protein RP105 Regulates Lipopolysaccharide Signaling in B Cells. J. Exp. Med. 192: 23-30.

8. Hayashi, S. -I., K. Miyake, and P. W. Kincade. 2000. The CD9 molecule on stromal cells. Leukemia and Lymphoma. 38: 265-270.

9. Nomura, F., S. Akashi, Y. Sakao, S. Sato, T. Kawai, M. Matsumoto, K. Nakanishi, M. Kimoto, K. Miyake, K. Takeda, and S. Akira. 2000. Cutting Edge: Endotoxin tolerance in mouse peritoneal macrophages correlates with downregulation of surface TLR4 expression. J. Immunol. 164: 3476-3479.

10. Akashi, S., R. Shimazu, H. Ogata, Y. Nagai, K. Takeda, M. Kimoto, and K. Miyake. 2000. Cutting Edge: Cell surface expression and LPS signaling via the Toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J. Immunol. 164: 3471-3475.

11. Akashi, S., H. Ogata, K. Fumiko, T. Kirikae, K. Kawasaki, M. Nishijima, R. Shimazu, Y. Nagai, K. Fukudome, M. Kimoto and K. Miyake. 2000. Regulatory roles for CD14 and phosphatidylinositol in the signaling via Toll-like Receptor 4-MD-2. Biochem. Biophys. Res. Commu. 268:172-177.

12. Kawasaki, K., S. Akashi, R. Shimazu, T. Yoshida, K. Miyake, and M. Nishijima. 2000. Mouse TLR4-MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem. 275:2251-2254.

13. Yashiro-Ohtani, Y., X. -Y. Zhou, K. Toyo-oka, X. -G. Tai, C. -S. Park, T. Hamaoka, R. Abe, K. Miyake, and H. Fujiwara. 2000. Non-CD28 costimulatory molecules present in T cell rafts in duce T cell costimulation by enhancing the association of T cell receptor with rafts. J. Immunol. 164: 1251-1259.

14. Miyake K, Ogata H, Nagai Y, Akashi S, Kimoto M. 2000. Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. Journal of Endotoxin Research, vol.6, No.5,

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1999

1. Toyo-oka, K., Y. Yashiro-Ohtani, P. C. -S. Park, X. -G. Tai, K. Miyake, T. Hamaoka, and H. Fujiwara. 1999. Association of a tetraspanin CD9 with CD5 on the T cell surface: role of particular transmembrane domains in the association. Int. Immunol. 11: 2043-2052.

2. Koarada, S., Y. Tada, O. Ushiyama, F. Morito, N. Suzuki, A. Ohta, K. Miyake, M. Kimoto, and K. Nagasawa. 1999. B cells lacking RP105, a novel B cell antigen, in systemic lupus erythematosus. Arthritis Rheum. 42: 2593-2600.

3. Shimazu, R., S. Akashi, H. Ogata, Y. Nagai, K. Fukudome, K. Miyake, and M. Kimoto. 1999. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189: 1777-1782.

4. Tanio, Y., H. Yamazaki, T. Kunisada, K. Miyake, and S. -I. Hayashi. 1999. CD9 molecule expressed on stromal cells is involved in osteoclastogenesis. Exp. Hematol. 27:853-859.

5. Ogata, M., T. Takada, Y. Mori, M. Oh-hora, Y. Uchida, A. Kosugi, K. Miyake, and T. Hamaoka. 1999. Effects of overexpression of PTP36, a putative protein tyrosine phosphatase, on cell adhesion, cell growth, and cytoskeletons in HeLa cells. J. Biol. Chem. 274: 12905-12909.

6. Aoyama, K., K. Oritani, T. Yokota, J. Ishikawa, T. Nishiura, K. Miyake, Y. Kanakura, Y. Tomiyama, P. W. Kincade, and Y. Matsuzawa. 1999 Stromal cell CD9 regulates differentiation of hematopoietic stem/progenitor cells. Blood 93: 2586-2594.

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