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2004 Fiscal Year Final Research Report Summary

Treatment of endotoxin-induced tissue damages by the negative regulation of TLR-mediated signal pathways

Research Project

Project/Area Number 15390220
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General internal medicine (including Psychosomatic medicine)
Research InstitutionHYOGO COLLEGE OF MEDICINE

Principal Investigator

TSUTSUI Hiroko  HYOGO COLLEGE OF MEDICINE, FACULTY OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 助教授 (40236914)

Co-Investigator(Kenkyū-buntansha) YASUDA Koubun  HYOGO COLLEGE OF MEDICINE, FACULTY OF MEDICINE, RESEARCH ASSOCIATE, 医学部, 助手 (50333539)
NAKANISHI Kenji  HYOGO COLLEGE OF MEDICINE, FACULTY OF MEDICINE, PROFESSOR, 医学部, 教授 (60172350)
Project Period (FY) 2003 – 2004
KeywordsToll-like receotors / Myeloiddifferentiation factor 88 / liver injuries / liver regeneration / SOCS-1 / SOCS-3 / LPS / Reactivearthritis
Research Abstract

Immunity is largely categorized into two types, adoptive immunity and innate immunity. As compared with innate immunity, acquired immunity has the diversity and the accuracy in its recognition of corresponding antigens based on the DNA rearrangement machineries and hypermutation properties that T cells and B cells selectively possess. Therefore, acquired immunity had been believed to he extremely sophisticated and ideal system for host defense. Innate immunity had been regarded to play a role only as the front line that would drop out after activation of the corresponding acquired immunity. In fact, innate immune constituents, such as dendritic cells(DCs) and macrophages, can promptly respond to microbes and their products without help from additional acquired immune responses, whereas acquired immunity takes long time to be able to exert its full immunological actions. However, recent intensive studies on signaling receptors in the innate immune system, in particular on toll-like rece … More ptors(TLRs), led us to notify its importance comparable to adaptive immunity. After microbial infection, antigen-presenting cells(APCs) composing innate immunity capture the microbial antigens. Simultaneously, the microbial products stimulate the APCs through their TLRs to undergo the appropriate maturation, which is represented by expression of chemokine receptors critical for translocation into the regional lymph nodes and of various co-stimulatory molecules essential for the appropriate activation of T helper cells. These APCs produce a variety of cytokines in response to the TLR ligands of the microbes as well. Unless they experience these biological events through their TLRs, these APCs cannot drive the activation or differentiation of antigen-specific T cells. In particular, certain cytokines, such as IL-12 and IL-18, produced by the APCs are required for the differentiation of naive helper T cells toward the effector cells to eradicate the microbes. Thus, the absence of innate immune responses render mammalian host highly susceptible to pathological organisms.
Innate immunity is equipped with various signaling receptors including a TLR family (Janeway and Medzhitov,2002). TLR family consists of more than 10 members. Each member precisely recognizes corresponding molecular patterns associated with pathogens, and exerts its host defensive actions based on their ignorance of host-derived intact components. Indeed, the TLR-mediated signal pathways are essential for microbe expulsion at the early infectious phase. Unexpectedly and importantly, the signalings through TLRs are definitely required for the following activation of the acquired immunity. Lack of the TLR-mediated pathway sometimes causes immature T cell responses and failure in the development of memory T cells, presumably due to the absence of cytokine production and DC maturation and activation, which is normally induced by the activation of the TLR pathway and is required for those immunological events.
Like in the case of autoimmunity associated with the dysregulated adaptive immunity, excessive activation of innate immunity causes diseases. It is well documented that the activation of innate immunity by pathogens occasionally causes fatal pathological alterations via aberrant induction of cytokines. Both innate and acquired immune systems complete their proper actions via cognate cellular interactions and cytokine catch bowl. Therefore, it is quite important for homeostatic immune responses to regulate the innate immune responses and adaptive immunity by controlling TLR and cytokine signalings.
In this study, we demonstrated that TLR-mediated signaling are essential for the tissue homeostasis in mice. Upon partial hepatectomy, wild-type mice show prompt liver regeneration. However, mutant mice that lack intracellular adaptor molecule essential for the activation of TLR-mediated pathways are defect in the liver regeneration after partial hepatectomy. This clearly indicates that TLR-mediated innate immunity is essential for not only host defense but also tissue homeostasis. Furthermore, we observed that IL-6 but not TNF, both of which are induced by the activation of TLR-mediated signalings, contributes to the development of acute reactive arthritis in mice. Thus, these results indicate that the TLR-mediated pathways play an important role in various biological situations, such as host defense, tissue homeostasis and incidental tissue injuries. Less

  • Research Products

    (45 results)

All 2005 2004 2003

All Journal Article (42 results) Book (3 results)

  • [Journal Article] Contribution of Toll-like receptor/Myeloid differentiation factor 88 signallings to liver regeneration.2005

    • Author(s)
      Seki, E., Tsutsui, H., 他
    • Journal Title

      Hepatology 41

      Pages: 443-450

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Editorial : TNF signaling as pleiotropic gates in the liver.2005

    • Author(s)
      Tsutsui, H.
    • Journal Title

      Hepatol.Res. 31

      Pages: 121-123

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A novel caspase-1/Toll-like receptor 4-independent pathway of cell death induced by cytosolic Shigella in infected macrophages.2005

    • Author(s)
      Suzuki, T., Nakanishi, K., 他
    • Journal Title

      J.Biol.Chem. 280

      Pages: 14042-14050

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Roles of Sema4A in the Immune System : Defective T Cell Priming and Th1/Th2 Regulation in Sema4A-Deficient Mice.2005

    • Author(s)
      Kumanogoh, A., Shikina, T., 他
    • Journal Title

      Immunity 22

      Pages: 305-316

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Endogenous IL-6 but not TNF-α contributes to the development of TLR4/MyD88-mediated acute arthritis in mice.2005

    • Author(s)
      Kyo, F., Futani, H., 他
    • Journal Title

      Arthritis & Rheum. (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Negative regulation of cytokine signalings by SOCS.2005

    • Author(s)
      Naka, T., Fujimoto, M., 他
    • Journal Title

      Adv.Immunol. 87

      Pages: 61-121

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Contribution of Toll-like receptor/Myeloid differentiation factor 88 signallings to liver regeneration.2005

    • Author(s)
      Seki, E, Tsutsui, H., Iimuro, Y., Naka, T., Son, G., Akira, S., Kishimoto, T., Nakanishi, K., Fujimoto, J.
    • Journal Title

      Hepatology 41

      Pages: 443-450

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Roles of Sema4A in the Immune System : Defective T Cell Priming and Th1/Th2 Regulation in Sema4A-Deficient Mice.2005

    • Author(s)
      Kumanogoh, A., Shikina, T., Suzuki, K., Uematsu, S., Yukawa, K., Kashiwamura, S., Tsutsui, H., Yamamoto, M., Takamatsu, H., Ko-Mitamura, EP., Takegahara, N., Marukawa, S., Ishida, I., Morishita, H., Prasad, DV., Tamura, M., Mizui, M., Toyofuku, T., Akira, S., Takeda, K., Okabe, M., Kikutani, H.
    • Journal Title

      Immunity. 22

      Pages: 305-316

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A novel caspase-1/Toll-like receptor 4-independent pathway of cell death induced by cytosolic Shigella in infected macrophages.2005

    • Author(s)
      Suzuki, T., Nakanishi, K., Tsutsui, H., Iwai, H., Akira, S., Inohara, N., Chamaillard, M., Nunez, G., Sasakawa C.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 14042-14050

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Endogenous IL-6 but not TNF-α contributes to the development of TLR4/MyD88-mediated acute arthritis in mice.2005

    • Author(s)
      Kyo, F., Futani, H., Matsui, K., Terada, M., Adachi, K., Nagata, K., Sano, H., Tateishi, H., Tsutsui, H., Nakanishi, K.
    • Journal Title

      Arthritis & Rheum. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A murine model of NKT cell-mediated liver injury induced by α-galactosylceramide/D-galactosamine.2005

    • Author(s)
      Fujii, H., Seki, S., Adachi, K., Tsutsui, H., Fujiwara, H., Ikarashi, Y., Taniguchi, M., Arakawa, T., Kobayashi, S., Kitada, T.
    • Journal Title

      Virchows Archiv. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Negative regulation of cytokine signalings by SOCS.2005

    • Author(s)
      Naka, T., Fujimoto, M., Tsutsui, H., Yoshimura, A.
    • Journal Title

      Advances in Immunol. 87

      Pages: 61-121

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases.2004

    • Author(s)
      Fujimoto, M., Tsutsui, H., 他
    • Journal Title

      Int.Immunol. 16

      Pages: 303-314

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Roles of caspase-1 in Listeria infection in mice.2004

    • Author(s)
      Tsuji, N.M., Tsutsui, H., 他
    • Journal Title

      Int.Immunol. 16

      Pages: 335-343

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Differential upregulation of interleukin-18 receptor alpha chain between CD4(+) and CD8(+) T cells during acute Graft-Host Disease in mice.2004

    • Author(s)
      Itoi, H., Fujimori, Y., 他
    • Journal Title

      J.Interferon Cytokine Res. 24

      Pages: 291-296

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Contribution of CD1d-unrestricted hepatic DX5^+ NKT cells to liver injury in Plasmodium berghei-parasitized erythrocyte-injected mice.2004

    • Author(s)
      Adachi, K., Tsutsui, H., 他
    • Journal Title

      Int.Immunol. 16

      Pages: 787-798

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Involvement of interleukin-18 in acute graft-versus-host disease in mice.2004

    • Author(s)
      Itoi, H., Fujimori, Y., 他
    • Journal Title

      Transplantation 78

      Pages: 1245-1250

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Inhibition by interleukin-18 of the growth of Dunn osteosarcoma cells.2004

    • Author(s)
      Okamoto, T., Yamada, N., 他
    • Journal Title

      J.Interferon Cytokine Res. 24

      Pages: 161-167

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Adult Still's disease reflects a Th2 rather than a Th1 cytokine profile.2004

    • Author(s)
      Saiki, O., Uda, H., 他
    • Journal Title

      Clin Immunol. 112

      Pages: 120-125

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules.2004

    • Author(s)
      Yamamoto, M., Yaginuma, K., 他
    • Journal Title

      Genes to Cells 9

      Pages: 1055-1067

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Induction of allergic inflammation by IL-18 in experimental animal models.2004

    • Author(s)
      Tsutsui, H., Yoshimoto, T., 他
    • Journal Title

      Immunol.Rev. 202

      Pages: 115-138

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Roles of caspase-1 in Listeria infection in mice.2004

    • Author(s)
      Tsuji, N.M., Tsutsui, H., Seki, E., Kuida, K., Okamura, H., Nakanishi, K., Flavell, R.A.
    • Journal Title

      Int.Immunol. 16

      Pages: 335-343

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases.2004

    • Author(s)
      Fujimoto, M., Tsutsui, H., Xinshou, O., Tokumoto, M., Watanabe, D., Shima, Y., Yoshimoto, T., Hirakata, H., Kawase, I., Nakanishi, K., Kishimoto, T., Naka, T.
    • Journal Title

      Int.Immunol. 16

      Pages: 303-314

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Contribution of CD1d-unrestricted hepatic DX5^+ NKT cells to liver injury in Plasmodium berghei-parasitized erythrocyte-injected mice.2004

    • Author(s)
      Adachi, K., Tsutsui, H., Seki, E., Nakano, H., Takeda, K., Okumura, K., Van Kaer L., Nakanishi, K.
    • Journal Title

      Int.Immunol. 16

      Pages: 787-798

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Inhibition by interleukin-18 of the growth of Dunn osteosarcoma cells.2004

    • Author(s)
      Okamoto, T., Yamada, N., Tsujimura, T., Sugihara, A., Nishizawa, Y., Ueda, H, Kashiwamura, S., Tsutsui, H., Futani, H., Maruo, S., Okamura, h., Terada, N.
    • Journal Title

      J.Interferon Cytokine Res. 24

      Pages: 161-167

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Differential upregulation of interleukin-18 receptor alpha chain between CD4(+) and CD8(+) T cells during acute Graft-Versus-Host Disease in mice.2004

    • Author(s)
      Itoi, H., Fujimori, Y., Tsutsui, H., Matsui, K., Hada, T., Kakishita, E., Okamura, H., Hara, H., Nakanishi, K.
    • Journal Title

      J.Interferon Cytokine Res. 24

      Pages: 291-296

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Adult Still's disease reflects a Th2 rather than a Th1 cytokine profile.2004

    • Author(s)
      Saiki, O., Uda, H., Nishimoto, N., Miwa, T., Mima, T., Ogawara, T., Azuma, N., Katada, Y., Sawaki, J., Tsutsui, H., Matsui, K., Maeda, A., Nakanishi, K.
    • Journal Title

      Clin Immunol. 112

      Pages: 120-125

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] ASC is essential for LPS-induced activation of procaspase-lindependently of TLR-associated signal adaptor molecules.2004

    • Author(s)
      Yamamoto, M., Yaginuma, K., Tsutsui, H., Sagaral, J., Guan, X., Seki, E., Yasuda, K., Yamamoto, M., Akira, S., Nakanishi, K., Noda, T., Taniguchi, S.
    • Journal Title

      Genes Cells. 9

      Pages: 1055-1067

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Involvement of interleukin-18 in acute graft-versus-host disease in mice.2004

    • Author(s)
      Itoi, H., Fujimori, Y., Tsutsui, H., Matsui, K., Sugihara, A., Terada, N., Hada, T., Kakishita, E., Okamura, H., Hara, H., Nakanishi, K.
    • Journal Title

      Transplantation 78

      Pages: 1245-1250

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Induction of allergic inflammation by IL-18 in experimental animal models.2004

    • Author(s)
      Tsutsui, H, Yoshimoto, T., Hayashi, N., Mizutani, H., Nakanishi, K.
    • Journal Title

      Immunological Review 202

      Pages: 115-138

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] TNF signaling as pleiotropic gates in the liver.2004

    • Author(s)
      Tsutsui, H. Editorial
    • Journal Title

      Hepatol.Res. 31

      Pages: 121-123

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] TGF beta down-regulates IFN-gamma production in IL-18 treated NK cell line LNK5E6.2003

    • Author(s)
      Hayashi, H., Inoue, Y., 他
    • Journal Title

      Biochem.Biophys.Res.Commun. 300

      Pages: 980-985

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Nuclear factor κB decoy oligodeoxynucleotides prevent endotoxin-induced fatal liver failure in a murine model.2003

    • Author(s)
      Ogushi, I., Iimuro, Y., 他
    • Journal Title

      Hepatology 38

      Pages: 335-344

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Persistent secretion of IL-18 in the skin contributes to systemic IgE response in mice.2003

    • Author(s)
      Nakano, H., Tsutsui, H., 他
    • Journal Title

      Int.Immunol. 15

      Pages: 611-621

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cytokine-induced inflammatory liver injury.2003

    • Author(s)
      Tsutsui, H., Adachi, K., 他
    • Journal Title

      Current Molecular Medicine 3

      Pages: 545-559

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Pathophysiological roles for IL-18 in inflammatory arthritis.2003

    • Author(s)
      Matsui, K., Tsutsui, H., 他
    • Journal Title

      Expert Opinion on Therapeutic Targets 7

      Pages: 701-724

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] TGFβ down-regulates IFN-γ production in IL-18 treated NK cell line LNK5E6.2003

    • Author(s)
      Hayashi, H., Inoue, Y., Tsutsui, H., Okamura, H., Nakanishi, K., Onozaki, K.
    • Journal Title

      Biochem.Biophys.Res.Commun. 300

      Pages: 980-985

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Persistent secretion of IL-18 in the skin contributes to systemic IgE response in mice.2003

    • Author(s)
      Nakano, H., Tsutsui, H., Terada, M., Yasuda, K., Matsui, K., Yumikura-Futatsugi, S., Yamanaka, K., Mizutani, H., Yamamura, T., Nakanishi, K.
    • Journal Title

      Int.Immunol. 15

      Pages: 611-621

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nuclear factor κ B decoy oligodeoxynucleotides prevent endotoxin-induced fatal liver failure in a murine model.2003

    • Author(s)
      Ogushi, I., Iimuro, Y., Seki, E., Sonm G., Hirano, T., Hada, T., Tsutsui, H., Nakanishi, K., Morishita, R., Kaneda, Y., Fujimoto, J.
    • Journal Title

      Hepatology 38

      Pages: 335-344

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Interleukin-18. [IL-1F4].2003

    • Author(s)
      Okamura, H., Lotze, M.T., Tsutsui, H., Kashiwamura, S-I., Ueda, H., Yoshimoto, T., Nakanishi, K.
    • Journal Title

      The cytokine handbook (4^<th> edition)(Thomson, A.W. and Lotze, M.T., eds)(Elsevier Science Ltd., London)

      Pages: 709-733

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] IL-18 and IL-18 Receptor Knockout Mouse.2003

    • Author(s)
      Tsutsui, H., Yoshimoto, T., Okamura, H., Akira, S., Nakanishi, K.
    • Journal Title

      Cytokine Knockouts (Giamila Fantuzzi, eds)(Humana Press, Totowa, New Jersey)

      Pages: 303-322

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Interlukin-18.2003

    • Author(s)
      Tsutsui, H., Yoshimoto, T., Okamura, H., Nakanishi, K.
    • Journal Title

      Encyclopedia of Hormones (HL.Henry and AW.Norman, eds.)(Elsevier Science)

      Pages: 493-500

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] IL-18 and IL-18 Receptor Knockout Mouse. In : Cytokine Knockouts2003

    • Author(s)
      Tsutsui, H., Yoshimoto, T., 他
    • Total Pages
      471
    • Publisher
      Human Press, Totowa, NJ
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] Interleukin-18. [IL-1F4] In : The cytokine handbook(4^<th> edition)2003

    • Author(s)
      Okamura, H., Lotze, M.T., 他
    • Total Pages
      1572
    • Publisher
      Elsevier Science Ltd.
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] Interlukin-18. In : Encyclopedia of Hormones2003

    • Author(s)
      Tsutsui, H., Yoshimoto, T., 他
    • Total Pages
      2154
    • Publisher
      Academic Press
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2006-07-11  

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