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.
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.
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.
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,
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.
1. Mine, M., S. Koarada, T. Sai, K. Miyake, and M. Kimoto. 1998. Peptide-binding motifs of the mixed haplotype Abz/Aad major histocompatibility complex class II molecule: a restriction element for auto-reactive T cells in (NZB x NZW)F1mice. Immunology 95: 577-584.
2. Miyamoto, A., T. Kunisada, H. Yamazaki, K. Miyake, S. Nishikawa, T. Sudo, L. D. Schultz, and S. -I. Hayashi. 1998. Establishment and characterization of pro-B cell lines from motheaten mutant mouse defective in SHP-1 protein tyrosine phosphatase. Immunol. Letters 63: 75-82.
3. Miura, Y., R. Shimazu, K. Miyake, S. Akashi, H. Ogata, Y. Yamashita, Y. Narisawa, and M. Kimoto. 1998. RP105 is associated with MD-1, and transmits an activation signal in human B Cells. Blood 92: 2815-2822.
4. Miyake, K., R. Shimazu, J. Kondo, T. Niki, S. Akashi, H. Ogata, Y. Yamashita, Y. Miura, and M. Kimoto. 1998. Mouse MD-1, a molecule that is physically associated with RP105 and positively regulates its expression. J. Immunol. 161: 1348-1353.
5. Chan, V.W.F., I. Mecklenbrauker, Ih. Su, G. Texido, M. Leitges, R. Carsetti, C. A. Lowell, K. Rajewsky, K. Miyake, and A. Tarakhovsky. 1998. The molecular mechanism of B cell activation by toll-like receptor protein RP-105. J. Exp. Med. 188: 93-101.
6. Kosugi, A., S. Saitoh, S. Noda, K. Miyake, Y. Yamashita, M. Kimoto, M. Ogata, and T. Hamaoka 1998. Physical and functional association between thymic shared antigen-1/stem cell antigen-2 and the T cell receptor complex. J. Biol. Chem. 273: 12301-12306.
7. Miyamoto, A., T. Kunisada, H. Hemmi, T. Yamane, H. Yasuda, K. Miyake, H. Yamazaki, and S. I. Hayashi. 1998. Establishment and characterization of an immortal macrophage-like cell line inducible to differentiate to osteoclasts. Biochem. Biophys. Res. Commu. 242: 703-709.
8. Grumont, R. J., I. J. Rourke, L. A. O'Reilly, A. Strasser, K. Miyake, W. Sha, and S. Gerondakis. 1998. B lymphocytes differentially use the rel and nuclear factor kB1 (NFkB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J. Exp. Med. 187: 663-674.
1. Fukuoka, M., M. Tokushima, S. Koarada, T. Sai, K. Miyake, and M. Kimoto. 1997. Analysis of Vb4 T cell receptor CDR3 repertoire in BALB/c and (NZB x NZW)F1 mice. Immunol. Letters 59: 63-69.
2. Yasue, T., H. Nishizumi, S. Aizawa, T. Yamamoto, K. Miyake, C. Mizoguchi, S. Uehara, Y. Kikuchi, and K. Takatsu. 1997 A critical role of Lyn and Fyn for B cell responses to CD38 ligation and interleukin 5. Proc. Natl. Acad. Sci. USA 94: 10307-10312.
1. Miura, Y., K. Miyake, Y. Yamashita, R. Shimazu, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, J. Inazawa, T. Abe, and M. Kimoto. 1996. Molecular cloning of a human RP105 homologue and chromosomal localization of the mouse and human RP105 genes (Ly64 and LY64). Genomics 38: 299-304.
2. Miyakawa, Y., T. Nishimura, Y. Ueyama, K. Miyake, M. Miyasaka, Y. Ikeda, and S. Habu. 1996. Cell adhesion via murine α4 human β1 integrin chimera on transfected K562 cells to endothelial cells. Exp. Cell Res. 226: 75-79.
3. Yamashita, Y., K. Miyake, Y. Miura, Y. Kaneko, H. Yagita, T. Suda, S. Nagata, J. Nomura, N. Sakaguchi, and M. Kimoto. 1996. Activation Mediated by RP105 but Not CD40 Makes Normal B cells Susceptible to Anti-IgM-induced Apoptosis: A Role for Fc Receptor Coligation. J. Exp. Med. 184:113-120.
4. Oritani, K., X. Wu, K. Medina, J. Hudson, K. Miyake, J. M. Gimble, S. A. Burstein, and P. W. Kincade. 1996. Antibody ligation of CD9 modifies production of myeloid cells in long-term culture. Blood 87:2252-2261.
1. Kikuchi, Y., T. Yasue, K. Miyake, M. Kimoto, and K. Takatsu. 1995. CD38 ligation induces tyrosine phosphorylation of Bruton tyrosine kinase and enhanced expression of interleukin 5-receptor α chain: Synergistic effects with interleukin 5. Proc. Natl. Acad. Sci. USA 92: 11814-11818.
2. Satoh, S., A. Kosugi, S. Noda, N. Yamamoto, M. Ogata, Y. Minami, K. Miyake, and T. Hamaoka. 1995. Modulation of TCR-mediated signaling pathway by thymic shared antigen-1 (TSA-1)/stem cell antigen-1 (Sca-2). J. Immunol. 155: 5574-5581.
3. Zheng, Z., S. Katoh, Q. He, K. Oritani, K. Miyake, J. Lesley, R. Hyman, A. Hamik, R. M. E. Parkhouse, A. G. Farr, and P. W. Kincade. 1995. Monoclonal antibodies to CD44 and their influence on hyaluronan recognition. J. Cell Biol. 130: 485-495.
4. Yamashita, Y., K. Miyake, Y. Kikuchi, K. Takatsu, S. Noda, A. Kosugi, and M. Kimoto. 1995. A monoclonal antibody against a murine CD38 homologue delivers a signal into B cells for prolongation of survival and protection against apoptosis in vitro: unresponsiveness of X-linked immunodeficient B cells. Immunology 85: 248-255.
5. Miyake, K., Y. Yamashita, M. Ogata, T. Sudo, and M. Kimoto. 1995. RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family. J. Immunol. 154: 3333-3340.
1. Miyake, K., Y. Yamashita, Y. Hitoshi, K. Takatsu, and M. Kimoto. 1994. Murine B cell proliferation and protection from apoptosis with an antibody against a 105 kDa molecule: unresponsiveness of X-linked immunodeficient B cells. J. Exp. Med. 180: 1217-1224.
2. Kosugi, A., S. Saitoh, S. Narumiya, K. Miyake, and T. Hamaoka. 1994. Activation-induced expression of thymic shared antigen-1 on T lymphocytes and its inhibitory role for TCR-mediated IL-2 production. Int. Immunol. 6: 1967-1976.
3. Naitoh, K., Y. Ichigi, K. Miyake, A. Muraguchi, and M. Kimoto. 1994. Signal transmission through MHC class II molecules in a human B lymphoid progenitor cell line: Different signaling pathways depending on the maturational stages of B cells. Microbiol. Immunol. 38: 967-976.
4. Tokushima, M., S. Koarada, S. Hirose, Y. Gotoh, H. Nishimura, K. Miyake, and M. Kimoto. 1994. In vivo induction of IgG anti-DNA antibody by autoreactive mixed haplotype Aβz/Aαd MHC class II molecule-specific CD4+ T-cell clones. Immunology. 83: 221-226.
5. Wu, X., K. Miyake, K. L. Medina, P. W. Kincade, and J. M. Gimble. 1994. Recognition of murine integrin β1 by a rat anti-stromal monoclonal antibody. Hybridoma 13: 409-416.
6. Miyake, K., Y. Yamashita, and M. Kimoto. 1994. A calcium- or manganese-dependent epitope on the integrin β1 chain recognized by a unique mAb. Int. Immunol. 6: 1221-1226.
7. Okahara, H., H. Yagita, K. Miyake, and K. Okumura. 1994. Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor a enhancement of experimental metastasis. Cancer Res. 54: 3233-3236.
8. Narumiya, S., Y. Abe, Y. Kita, K. Miyake, K. Nakajima, T.X. Watanabe, Y. Oka, H. Sugiyama, H. Yagita, K. Okumura, T. Hamaoka, and H. Fujiwara. 1994. Pre-B cells adhere to fibronectin via interactions of integrin a5/aV with RGDS as well as of integrin a4 with two distinct V region sequences at its different binding sites. Int. Immunol. 6:139-147.