Pattern-recognition receptors in dendritic cells evoke cellular immunity in response to viral RNA patterns

• Project/Area Number: 19209015
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Hokkaido University
• Principal Investigator: SEYA Tsukasa Hokkaido University, 大学院・医学研究科, 教授 (10301805)
• Co-Investigator(Kenkyū-buntansha): MATSUMOTO Misako 北海道大学, 大学院・医学研究科, 准教授 (30332456) ; AKAZAWA Takashi 大阪府立成人病センター, 研究所, 大阪府研究職 (80359299)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥48,620,000 (Direct Cost: ¥37,400,000、Indirect Cost: ¥11,220,000); Fiscal Year 2009: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2008: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2007: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
• Keywords: 自然免疫 / TLR / TICAM-1 / IPS-1 / 樹状細胞 / NK細胞 / RNAパターン認識 / ワクチン / Toll-like receptor / TICAM-1経路 / Toll-like-receptor / Myd88経路 / polyI:C / TICAM-1(TRIF) / NK activation / Dendritic cell / RNA adjuvant / antitumor therapy / interferon (IFN) / adoptive transfer

Research Abstract

How host cells respond to viral dsRNA is analyzed in this study. Dendritic cells (DC) stimulated with polyI : C (an dsRNA analog) render the DC competent for NK activation. Since cell-cell contact was essential for this NK activation, the molecule expressed on DC to drive NK activation was identified from genes up-regulated by polyI : C stimulation. Ultimately, we identified a membrane protein responsible for NK induction and named it INAM. INAM is a tetraspanin-like molecule inducing NK tumoricidal activity and in vivo tumor regression.

Research Products

• [Journal Article] Molecular mechanism for activation of Toll/IL-1 receptor domain-containing adaptor molecule-1 (TICAM-1) (2010)
  • Author(s): Tatematsu, M., A. Ishii, M. Horiuchi, H. Oshiumi, F. Inagaki, T. Seva, M. Matsumoto.
  • Journal Title: J. Biol. Chem. (in press)
• [Journal Article] Adjuvant engineering for cancer immunotherapy : development of a synthetic TLR2 ligand with increased cell adhesion (2010)
  • Author(s): Akazawa, T., N. Inoue, H. Shime, K. Sugiura, K. Kodama, M. Matsumoto, T. Seya.
  • Journal Title: Cancer Sci (in press)
  • NAID: 10026594411
• [Journal Article] DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta inducing potential (2010)
  • Author(s): Oshiumi, H., K. Sakai, M. Matsumoto, T. Seya.
  • Journal Title: Eur. J Immunol (in press)
• [Journal Article] Identification of INAM, a polyI : C-inducible membrane protein, that participates in dendritic cell-mediated natural killer cell activation (2010)
  • Author(s): Ebihara, T., M. Azuma, H. Oshiumi, M. Matsumoto, T. Seva.
  • Journal Title: J. Exp. Med. (in press)
• [Journal Article] Innate immunity and vaccine (2010)
  • Author(s): Seva, T.
  • Journal Title: Vaccine (in press)
• [Journal Article] Pattern-recognition receptors of innate immunity and their application to tumor immunotherapy (2010)
  • Author(s): Seva, T., H. Shime, T. Ebihara, H. Oshiumi, M. Matsumoto.
  • Journal Title: Cancer Sci. 101 Pages: 313-320
  • NAID: 10026587432
• [Journal Article] Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor of the Toll-like receptor 3/4 pathway (2010)
  • Author(s): Sasai, M., H. Oshiumi, K. Funami, M. Matsumoto, T. Seya.
  • Journal Title: Molec. Immunol. 47 Pages: 1283-1291
• [Journal Article] Identification of INAM, a polyI : C-inducible membrane protein, that participates in dendritic cell-mediated natural killer cell activation. (2010)
  • Author(s): Ebihara, T., M.Azuma, H.Oshiumi, M.Matsumoto, T.Seya
  • Journal Title: J.Exp.Med (in press)
  • Peer Reviewed
• [Journal Article] DEAD/H BOX 3(DDX3)helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta inducing potential. (2010)
  • Author(s): Oshiumi, H., K.Sakai, M.Matsumoto, T.Seya
  • Journal Title: Eur.J.Immunol. (in press)
  • Peer Reviewed
• [Journal Article] Adjuvant engineering for cancer immunotherapy : development of a synthetic TLR2 ligand with increased cell adhesion. (2010)
  • Author(s): Akazawa, T., N.Inoue, H.Shime, K.Sugiura, K.Kodama, M.Matsumoto, T.Seya
  • Journal Title: Cancer Science (in press)
  • NAID: 10026594411
• [Journal Article] Dendritic cell-derived TNF-α is responsible for development of IL-10-producing CD4+ T cells. (2010)
  • Author(s): Hirata, N., Y.Yanagawa, M.Satoh, H.Ogura, T.Ebihara, M.Noguchi, M.Matsumoto, H.Togashi, T.Seya, K.Ono, K.Iwabuchi
  • Journal Title: Cell.Immunol. 261 Pages: 37-41
  • NAID: 120001875433
  • Peer Reviewed
• [Journal Article] Pattern recognition receptors of innate immunity and their application to tumor immunotherapy. (2010)
  • Author(s): Seya, T., H.Shime, T.Ebihara, H.Oshiumi, M.Matsumoto.
  • Journal Title: Cancer Science 101 Pages: 313-320
  • NAID: 10026587432
• [Journal Article] IL-6 and IFN-alpha from dsRNA-stimulated dendritic cells control expansion of regulatory T cells. (2010)
  • Author(s): Kubota, N., T.Ebihara, M.Matsumoto, S.Gando, T.Seya.
  • Journal Title: Biochem.Biophys.Res.Commun. 391 Pages: 1421-1426
  • Peer Reviewed
• [Journal Article] Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathway. (2010)
  • Author(s): Sasai, M., M.Tatematsu, H.Oshiumi, K.Funami, M.Matsumoto, T.Seya.
  • Journal Title: Molec.Immunol. 47 Pages: 1283-1291
  • Peer Reviewed
• [Journal Article] Innate immune therapy with a BCG cell wall skeleton for lung cancer : a case presentation and a case control study (2009)
  • Author(s): Kodama, K., M. Higashiyama, K. Takami, K. Oda, J. Okami, J. Maeda, T. Akazawa, M. Matsumoto, T. Seya, M. Wada, A. Hayashi, K. Toyoshima.
  • Journal Title: Surgery Today. 39 Pages: 194-200
• [Journal Article] Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3 (2009)
  • Author(s): Iwakiri. D., L. Zhou, M. Samanta, M. Matsumoto, T. Ebihara, T. Seya, S. Imai, M. Fujieda, K. Kawa, K. Takada.
  • Journal Title: J. Exp. Med. 206 Pages: 2091-2099
  • NAID: 120001629790
• [Journal Article] The extrinsic RNA-sensing pathway for adjuvant immunotherapy for cancer (2009)
  • Author(s): Seya. T., M. Matsumoto.
  • Journal Title: Cancer Immunol. Immunother. 58 Pages: 1175-1184
• [Journal Article] Functional evolution of the TICAM-1 (TRIF) pathway for extrinsic RNA sensing (2009)
  • Author(s): Seya. T., M. Matsumoto, T. Ebihara, H. Oshiumi.
  • Journal Title: Immunol. Rev. 227 Pages: 44-53
• [Journal Article] Cytoplasmic oligomerized TICAM-1 recruits nuclear BS69 to enhance type I interferon induction (2009)
  • Author(s): Takaki, H., H. Oshiumi, T. Kawanishi, M. Sasai, M. Matsumoto, T. Seya.
  • Journal Title: Eur. J. Immunol. 39 Pages: 3469-3476
• [Journal Article] Mitofusin 2, a mitochondrial fusion mediator, acts as a negative regulator for mitochondrial antiviral signaling (2009)
  • Author(s): Yasukawa, K., H. Oshiumi, M. Takeda, Y. Yanagi, T. Seya, S. Kawabata, T. Koshiba.
  • Journal Title: Science Signaling. 2(84)
• [Journal Article] Innate Immunostimulatory lipopepitdes of Staphylococcus aureus as TLR2 ligands ; Prediction with mRNA expression, chemical synthesis and immunostimulatory activities (2009)
  • Author(s): Fujimoto, Y., M. Hashimoto, M. Furuyashiki, M. Katsumoto, T. Seya, Y. Suda, K. Fukase.
  • Journal Title: Chem Bio Chem. 10 Pages: 2311-2315
• [Journal Article] Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice (2009)
  • Author(s): Akao, Y., T. Ebihara, H. Masuda, Y. Saeki, K. Hazeki, O. Hazeki, M. Matsumoto, T. Seya.
  • Journal Title: Cancer Sci. 100 Pages: 1494-1501
  • NAID: 10027193541
• [Journal Article] Obstructing shedding of the immune stimulatory MHC class I chain-related gene B prevents tumor formation (2009)
  • Author(s): Wu, J. D., C. L. Atteridge, X. J. Wang, T. Seya, S. R. Plymate
  • Journal Title: Clin. Cancer Res. 15 Pages: 632-640
• [Journal Article] Riplet/RNF135, a RING-finger protein, ubiquitinates RIG-I to promote interferon-β induction during the early phase of viral infection (2009)
  • Author(s): Oshiumi, H., M. Matsumoto, S. Hatakeyama, T. Seya.
  • Journal Title: J. Biol. Chem. 284 Pages: 807-817
• [Journal Article] Oligomerized Toll-interleukin 1 receptor domain(TIR)-containing adaptor molecule-1 in the cytoplasm recruits nuclear adenovirus 5E1A-binding protein to enhance NF-kB activation and type I IFN induction. (2009)
  • Author(s): Takaki, H., H.Oshiumi, M.Sasai, T.Kawanishi, M.Matsumoto, T.Seya.
  • Journal Title: Eur.J.Immunol. 39 Pages: 3469-3476
  • Peer Reviewed
• [Journal Article] Dendritic cell/NK cell interaction in RNA virus infection. (2009)
  • Author(s): Ebihara, T., M.Matsumoto, T.Seya.
  • Journal Title: Current Immunol.Reviews 5 Pages: 200-207
• [Journal Article] Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice. (2009)
  • Author(s): Akao Y., T.Ebihara, H.Masuda, Y.Saeki, T.Akazawa, K.Hazeki, O.Hazeki, M.Matsumoto, T.Seya.
  • Journal Title: Cancer Science 100 Pages: 1494-1501
  • NAID: 10027193541
  • Peer Reviewed
• [Journal Article] Riplet/RNF135, a RING-finger protein, ubiquitinates RIG-I to promote interferon-β induction during the early phase of viral infection. (2009)
  • Author(s): Oshiumi, H., M.Matsumoto, S.Hatakeyama, T.Seya.
  • Journal Title: J.Biol.Chem. 284 Pages: 807-817
  • Peer Reviewed
• [Journal Article] The extrinsic RNA-sensing pathway for adjuvant immunotherapy of cancer. (2009)
  • Author(s): Seya, T., M.Matsumoto.
  • Journal Title: Cancer Immunol.Immunother. 58 Pages: 1175-1184
• [Journal Article] Functional evolution of the TICAM-1 pathway for extrinsic RNA sensing (2009)
  • Author(s): Seya, T., M.Matsumoto, T.Ebihara, H.Oshiumi.
  • Journal Title: Immunol.Reviews 227 Pages: 44-53
• [Journal Article] Epstein-Barr virus(EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3. (2009)
  • Author(s): Iwakiri, D., L.Zhou, M.Samanta, M.Matsumoto, T.Ebihara, T.Seya, S.Imai, M.Fujieda, K.Kawa, K.Takada.
  • Journal Title: J.Exp.Med. 206 Pages: 2091-2099
  • NAID: 120001629790
  • Peer Reviewed
• [Journal Article] Toll受容体の機能 (2009)
  • Author(s): 松本美佐子、瀬谷司
  • Journal Title: 生化学 81 Pages: 156-164
• [Journal Article] Mitofusin 2, a mitochondrial fusion mediator, acts as a negative regulator for mitochondrial antiviral signaling. (2009)
  • Author(s): Yasukawa, K., H.Oshiumi, M.Takeda, Y.Yanagi, T.Seya, S.Kawabata, T.Koshiba
  • Journal Title: Science Signaling 2(84)
  • Peer Reviewed
• [Journal Article] Pan-vertebrate Toll-like receptors during evolution. (review) (2009)
  • Author(s): Oshiumi, H., Seya, T., et.al.
  • Journal Title: Curr. Genomics 9 Pages: 488-493
  • Peer Reviewed
• [Journal Article] RiPlet / RNF 135, a RING-finger Protein, ubiquitinates RIG-I to Promote interferon-β induction during the early phase of viral infection (2009)
  • Author(s): Oshiumi, H., Seva, T., et.al.
  • Journal Title: J. Biol. Chem. 284 Pages: 807-817
  • Peer Reviewed
• [Journal Article] Obstructing shedding of the immune stimulatory MHC class I chain?related gene B prevents tumor formation (2009)
  • Author(s): Wu, J. D., Seya, T., et.al.
  • Journal Title: Clin. Cancer Res. 15 Pages: 632-640
  • Peer Reviewed
• [Journal Article] Functional evolution of the TICAM-1 (TRIF) pathway. for extrins is RNA sensing. (review) (2009)
  • Author(s): Seya, T., et.al.
  • Journal Title: Immunol. Rev. 227 Pages: 44-53
  • Peer Reviewed
• [Journal Article] Innate immune therapy with a BCG cell wall skeleton after radical surgery for non-small cell lung cancer : a case?control study (2009)
  • Author(s): Kodama, K., Seya, T., et.al.
  • Journal Title: Surgery Today. 39 Pages: 194-200
  • Peer Reviewed
• [Journal Article] The extrinsic RNA-sensing pathway for adjuvant immunotherapy Of cancer. (review) (2009)
  • Author(s): Seya, T., et.al.
  • Journal Title: Cancer Immunol. Immunother. (in press)
  • Peer Reviewed
• [Journal Article] NK cell licensing by dendritic cell in RNA virus infection. (review) (2009)
  • Author(s): Ebihara, T., Seya, T., et.al.
  • Journal Title: Curr. Immunol. Rev. (in press)
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• [Journal Article] Regulator of Complement Activation (RCA) gene cluster in Xenop us tropicalis (2009)
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  • Journal Title: Immunogenetics (in press)
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• [Journal Article] Asp-Glu-Ala-Asp / His (DEAD / H) BOX 3 (DDX3) helicase assembles in the IFN-βpromoter stimulator-1 (IPS-1)Pathway to enhance IFN-β induction. (2009)
  • Author(s): Oshiumi, H., Seva, T., et.al.
  • Journal Title: PloS Pathol. (submitted)
  • Peer Reviewed
• [Journal Article] Specific recognition of diamilopimeric acid?containing peptidoglycan of Gram?negative bacteria by teleost Toll-like receptor 21 (2009)
  • Author(s): Matsuo, A., Seya, T., et.al.
  • Journal Title: PloS ONE. (submitted)
  • Peer Reviewed
• [Journal Article] Antitumor natural killer cell induction by orally administered Spirulina extract in mice (2009)
  • Author(s): Akao, Y., Seya, T., et.al.
  • Journal Title: Cancer Sci. (submitted)
  • Peer Reviewed
• [Journal Article] Teleost TLR22 recognizes RNA duplex to induce IFN and protect cells from birnaviruses (2008)
  • Author(s): Matsuo, A., H. Oshiumi, T. Tsujita, H. Mitani, H. Kasai, M. Yoshimizu, M. Matsumoto, T. Seya.
  • Journal Title: J. Immunol. 181 Pages: 3474-3485
• [Journal Article] Hepatitis C virus (HCV)-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells (2008)
  • Author(s): Ebihara, T., M. Shingai, M. Matsumoto, T. Wakita, T. Seya.
  • Journal Title: Hepatology. 48 Pages: 48-58
• [Journal Article] Homo-oligomerization is essential for Toll/IL-1 receptor domain containing adaptor molecule-1-mediated NF-kappaB and interferon regulatory factor-3 activation (2008)
  • Author(s): Funami K., M. Sasai, H. Oshiumi, T. Seya, M. Matsumoto
  • Journal Title: J. Biol. Chem. 283 Pages: 18283-18291
• [Journal Article] Modulation of Double-stranded RNA Recognition by the N-terminal Histidine-rich Region of the Human Toll-like Receptor 3 (2008)
  • Author(s): Fukuda, K., T. Watanabe, T. Tokisue, T. Tsujita, S. Nishikawa, T. Hasegawa, T. Seya, M. Matsumoto.
  • Journal Title: J. Biol. Chem. 283 Pages: 22787-22794
• [Journal Article] The clathrin-mediated endocytic pathway participates in dsRNA-induced IFN-b production (2008)
  • Author(s): Itoh, K., A. Watanabe, K. Funami, T. Seya, M. Matsumoto
  • Journal Title: J. Immunol. 181 Pages: 5522-5529
• [Journal Article] Tumor-secreted lactic acid promotes IL-23-IL-17 proinflammatory pathway (2008)
  • Author(s): Shime, H., M. Yabu, T. Akazawa, K. Kodama, M. Matsumoto, T. Seya, N. Inoue.
  • Journal Title: J. Immunol. 180 Pages: 7175-7183
• [Journal Article] Soluble G protein of respiratory syncytial virus inhibts Toll-like receptor 3/4-mediated IFN-beta induction (2008)
  • Author(s): Shingai, M., M. Azuma, T. Ebihara, M. Sasai, K. Funami, M. Ayata, H. Ogura, H. Tsutsumi, M. Matsumoto, T. Seya
  • Journal Title: Int. Immunol. 20 Pages: 1169-1180
• [Journal Article] The proinflammatory cytokine response to Chlamydia trachomatis elementary bodies in human macrophages is partly mediated by a lipoprotein, the macrophage infectivity potentiator, through TLR2/TLR1/TLR6 and CD14 (2008)
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• [Journal Article] Tumor-secreted lactic acid promotes IL-23-IL-17 proinflammatory pathway (2008)
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  • Peer Reviewed
• [Journal Article] Teleost TLR22 recognizes RNA duplex to induce IFN and protect cells from birnaviruses (2008)
  • Author(s): Matsuo, A., Seya, T., et.al.
  • Journal Title: J. Immunol. 181 Pages: 3474-3485
  • Peer Reviewed
• [Journal Article] Increased expression of Toll-like receptor3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers (2008)
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  • Journal Title: Hepatology International. 2 Pages: 222-230
  • Peer Reviewed
• [Journal Article] Homo-oligomerization is essential for Toll / IL-1 receptor domain containing adaptor molecule-1-mediated NF-kappaB and interferon regulatory factor-3 activation. (2008)
  • Author(s): Funami K., Seya, T., et.al.
  • Journal Title: J. Biol. Chem. 283 Pages: 18283-18291
  • Peer Reviewed
• [Journal Article] Modulation of Double-stranded RNA Recognition by the N-terminal Histidine-rich Region of the Human Toll-like Receptor 3. (2008)
  • Author(s): Fukuda, K., Seya, T., et.al.
  • Journal Title: J. Biol. Chem. 283 Pages: 22787-22794
  • Peer Reviewed
• [Journal Article] Hepatitis C virus (HCV)-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and NK cells (2008)
  • Author(s): Ebihara, T., Seya, T., et.al.
  • Journal Title: Hepatology. 48 Pages: 48-58
  • Peer Reviewed
• [Journal Article] Soluble G protein of respiratory syncytial virus inhibts Toll-like receptor 3/4-mediated IFN-beta induction. (2008)
  • Author(s): Shingai, M., Seya, T., et.al.
  • Journal Title: Int. Immunol. 20 Pages: 1169-1180
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• [Journal Article] Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells. (2008)
  • Author(s): Hirata, N., Seya, T., et.al.
  • Journal Title: Mol. Immunol. 45 Pages: 2734-2742
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• [Journal Article] The clathrin-mediated endocytic pathway participates in dsRNA-induced IFN-β production (2008)
  • Author(s): Itoh, K., Seva, T., et.al.
  • Journal Title: J.Immunol. 181 Pages: 5522-5529
  • Peer Reviewed
• [Journal Article] Tumor-secreted lactic acid promotes IL-23-IL-7 proinflammatory pathway (2008)
  • Author(s): Shime, H., et. al.
  • Journal Title: J. Immunol. 180 Pages: 7175-7183
  • Peer Reviewed
• [Journal Article] Hepatitis C virus (HCV)-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and NK cells (2008)
  • Author(s): Ebihara, T., et. al.
  • Journal Title: Hepatology 48 Pages: 48-58
  • Peer Reviewed
• [Journal Article] Homo-oligomerization is essential for Toll/IL-1 receptor domain containing adaptor molecule-1-mediated NF-kappaB and interferon regulatory factor-3 activation (2008)
  • Author(s): Funami K., et. al.
  • Journal Title: J. Biol. Chem. 283 Pages: 18283-18291
  • Peer Reviewed
• [Journal Article] The clathrin-mediated endocytic pathway participates in dsRNA-induced IFN-βproduction (2008)
  • Author(s): Itoh, K., et. al.
  • Journal Title: J. Immunol. 181 Pages: 5522-5529
  • Peer Reviewed
• [Journal Article] Obstructing shedding of the immune stimulatory MHC class Ichain-related gene B prevents tumor formation (2008)
  • Author(s): Wu, J. D., et. al.
  • Journal Title: Clin. Cancer Res. 15 Pages: 632-640
  • Peer Reviewed
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  • Journal Title: J Immunol. 179 Pages: 6867-6872
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  • Journal Title: Cancer Sci. 98 Pages: 1936-1942
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  • Journal Title: FEBS Lett. 581 Pages: 3334-3340
  • NAID: 120000955793
• [Journal Article] C-terminal LRRs of human Toll-like receptor 3 control receptor dimerization and signal transmission (2007)
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  • Journal Title: Molec. Immunol. 44 Pages: 3633-3640
• [Journal Article] Differential type I interferon (IFN) inducing abilities of wild-type vs. vaccine strains of measles virus (2007)
  • Author(s): Shingai, M., T. Ebihara, N. A. Begum, A. Kato,, T. Honma, K. Matsumoto, H. Saito, H. Ogura, M. Matsumoto, T Seya.
  • Journal Title: J. Immunol. 179 Pages: 6123-6133
• [Journal Article] Antitumor NK activation induced by the Toll-like receptor3-TICAM-1 (TRIF) pathway in myeloid dendritic cells (2007)
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  • Journal Title: Proc. Natl. Acad. Sci. USA. 104 Pages: 252-257
• [Journal Article] Toll-like receptor 3-mediated synthesis and release of eotaxin-1/CCL11 from human bronchial smooth muscle cells stimulated with double-stranded RNA (2007)
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  • Journal Title: J. Immunol. 178 Pages: 489-495
• [Journal Article] Lamprey Toll-like receptors with properties distinct from those of variable lymphocyte receptors (2007)
  • Author(s): Ishii, A., A. Matsuo, H. Sawa, T. Tsujita, K. Shida, M. Matsumoto, T. Seya.
  • Journal Title: J. Immunol. 178 Pages: 397-406
• [Remarks] ホームページ等
  • URL: http://www.hucc.hokudai.ac.jp/~e20536/