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Development of anti-skin ulcer drug based on the new concept -Application of the stimulatory effect of TNF-alpha on the production of NGF in fibroblasts

Research Project

Project/Area Number 07557378
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field 医薬分子機能学
Research InstitutionGifu Pharmaceutical University

Principal Investigator

KOHNO Michiaki  Gifu Pharmaceutical University, Cell Biology, Associate Professor, 薬学部, 助教授 (00027335)

Co-Investigator(Kenkyū-buntansha) NAKAZATO Hiroshi  Suntory Institute for Biomedical Research, Molecular Biology, Director, 生物医学研究所, 部長
TAKIGAWA Masahiro  Hamamatsu University School of Medicine, Dermatology, Professor, 医学部, 教授 (80115873)
HAYASHI Kyozo  Gifu Pharmaceutical University, Molecular Biology, Emeritus Professor, 薬学部, 名誉教授 (00029935)
SATO Masahiro  Gifu Pharmaceutical University, Cell Biology, Assistant Professor, 薬学部, 助手 (00240945)
辻本 雅文  理化学研究所, 主任研究員
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1996: ¥3,600,000 (Direct Cost: ¥3,600,000)
KeywordsTumor Necrosis factor-alpha / Nerve Growth Factor / Wound healing / Fibroblasts / Interleukin-1 / Bone Morphogenetic Protein / Receptor / Nerve regeneration
Research Abstract

(1) A possible interaction between TNF-alpha and other cytokines in stimulating the production of NGF in Swiss 3T3 cells was investigated. TNF-alpha's stimulatory activity on fibroblasts NGF production was synergized by IL-1alpha/beta, IFN-gamma and BMP-2, but was antagonized by TGF-beta. These findings reinforce the idea that TNF-alpha, in concert with IL-1alpha/beta, IFN-gamma and BMP-2, plays an essential role in regulating the regeneration of peripheral nerve following injury through an indirect mechanism by which it stimulates NGF production in fibroblasts.
(2) The role of the two types of TNF receptors, TNF-R1 and TNF-R2, in mediating the capacity of TNF to stimulate NGF productoin in fibroblasts was investigated. An agonistic anti-TNF-R1 antibody, but not an agonistic anti-TNF-R2 antibody, increased the NGF mRNA level and stimulated the NGF production in these cells, indicating that anti-TNF-R1 mediated the TNF's activity to stimulate the NGF gene expression. The post receptor signaling pathway leading to NGF gene expression, however, was unique and did not involve the activatoin of ERK MAP kinases, p38 MAP kinase, C kinase nor A kinase.
(3) The effect of topical TNF-alpha on cutaneous wound repair with special reference to regeneration of peripheral nerve was investigated in C57BL-KsJ (ab/db JcL) mice that spontaneously develop type II Diabetes Melitus by applying it to full thickness skin wound in dorsal skin. Regression rate of wound was significantly higher in mice treated with 100 ng/cm^2 TNF-alpha than control. However, wound worsened in mice that received 1 and 10 mug/cm^2 TNF-alpha. Furthermore, regeneration of peripheral nerve was more apparent in the TNF-alpha-treated (100 ng/cm^2) group as compared with control. These results suggests that TNF-alpha at appropriate concentrations is expected to accelerate cutaneous wound healing, especially in terms of nerve regeneration.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Iwasaki,S.: "Distribution and characterization of specific cellular binding proteins for bone morphogenetic protein-2." J.Biol.Chem.270. 5476-5482 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Chatani,Y.: "Cell-type specific modulation of cell growth by TGF-β does not correlate with mitogen-activated protein kinase activation." J.Biol.Chem.270. 30686-30692 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hattori,A.: "Bone morphogenetic protein-2 is markedly synergistic with tumor necrosis factor in stimulating the production of nerve growth factor in fibroblasts." Biochem.Mol.Biol.Int.38. 1095-1101 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hattori,A.: "Tumor necrosis factor(TNF)stimulates the production of nerve growth factor in fibroblasts via the 55-kDa type 1 TNF receptor." FEBS Lett.397. 157-160 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nagamine,K.: "Dissociation of c-fos induction and MAP kinase activation from HGF-induced motility response in human gastric carcinoma cells." Eur.J.Biochem.236. 476-481 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iwasaki,S.: "Characterization of the bone morphogenetic protein-2 as a neurotrophic factor. Induction of neuronal differentiation of PC12 cells in the absence of mitogen-activated protein kinase activation." J.Biol.Chem.271. 17360-17365 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iwasaki, S.et al.: "Distribution and characterization of specific cellular binding proteins for Bone Morphogenetic Protein-2" J.Biol.Chem.270. 5476-5482 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sano, M.et al.: "The activation and nuclear translocation of extracellular signal-regulated kinases (ERK-1 and -2) appear not to be required for elongation of neurites in PC12D cells" Brain Res.688. 213-218 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Oka, H.et al.: "Constitutive activation of Mitogen-activated protein (MAP) kinases in human renal cell carcinoma" Cancer Res.55. 4182-4187 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Chatani, Y.et al.: "Cell-type specific modulation of cell growth by TGF-beta1 dose not correlate with mitogen-activated protein kinase activation" J.Biol.Chem.270. 30686-30692 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Wakita, H.et al.: "Staphylococcal Enterotoxin B upregulates expression of ICAM-1 molecules on IFN-gamma-treated keratinocytes and keratinocyte cell lines" J.Invest.Dermatol.105. 536-542 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hattori, A.et al.: "Tumor necrosis factor (TNF) stimulates the production of nerve growth factor in fibroblasts via the 55-kDa type ITNF receptor" FEBS Lett.379. 157-160 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nagamine, K.et al.: "Dissociation of c-fos induction and MAP kinase activation from HGF-induced motility response in human gastric carcinoma cells" Eur.J.Biochem.236. 476-481 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hattori, A.et al.: "Bone morphogenetic protein-2 is markedly synergistic with tumor necrosis factor in stimulating the production of nerve growth factor in fibroblasts" Biochem.Mol.Biol.Int.38. 1095-1101 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iwasaki, S.et al.: "Characterization of the Bone Morphogenetic Protein-2 as a neurotrophic factor. Induction of neuronal differentiation of PC12 cells in the absence of mitogen-activated protein kinase activation" J.Biol.Chem.271. 17360-17365 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagi, H.et al.: "TCRVbeta7^+ Th2 cells mediate UVB-induced suppression of murine contact photosensitivity by releasing IL-10" J.Immunol.156. 1824-1831 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Koide, M.et al.: "Soluble form of vascular cell adhesion molecule-1 in systemic lupus erythematosus and discoid lupus erythematosus" J.Dermatol.Sci.12. 73-75 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hofmann, U.et al.: "Hair cycle-dependent changes in skin immune functions : Anagen-associated depression of sensitization for contact hypersensitivity in mice" J.Invest.Dermatol.106. 598-604 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Wakita, H.et al.: "Inhibitors of sphingolipid synthesis modulate Interferon (IFN)-gamma-induced intercellular adhesion molecules (ICAM)-1 and human leukocyte antigen (HLA)-DR expression on cultured normal human keratinocytes : Possible involvement of ceramide in biological action of IFN-gamma" J.Invest.Dermatol. 107. 336-342 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sakakura, C.et al.: "Induction of apoptosis by sphingosine, N,N-dimethylsphingosine, and epidermal growth factor in solid tumor cells : possible involvement of mitogen-activated protein kinase cascade in apoptotic signaling" Brit.J.Cancer. (in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iwasaki, S.: "Characterization of the Bone Morphogenetic Protein-2 as a neurotrophic factor. Induction of neuronal differentiation of PC12 cells in the absence of mitogen-activated protein kinase activation." J. Biol. Chem.271巻. 17360-17365 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hattori, A.: "Bone morphogenetic protein-2 is markedly synergistic with tumor necrosis factor in stimulating the production of nerve growth factor in fibroblasts." Biochem. Mol. Biol. Int.38巻. 1095-1101 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hattori, A.: "Tumor necrosis factor (TNF) stimulates the production of nerve growth factor in fibroblasts via the 55-kDa type 1 TNF receptor." FEBS Lett.379巻. 157-160 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nagamine, K.: "Dissociation of c-fos induction and MAP kinase activation from HGF-induced motility response in human gastric carcinoma cells." Eur. J. Biochem.236巻. 476-481 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sakakura, C.: "Induction of apoptosis by sphingosine, N, N-dimethysphingosine, and epidermal growth factor in solid tumor cells : A possible involvement of mitogen-activated protein kinase cascade in apoptotic signaling." Brit. J. Cancer. (in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Iwasaki,S.: "Distribution and characterization of specific cellular binding proteins for Bone Morphogenetic Protein-2." J.Biol.Chem.270. 5476-5482 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Sano,M.: "The activation and nuclear translocation of extracellular signal-regulated kinases(FRK-1 and -2) appear not to be required for elongation of neurites in PC12D cells," Brain Res.688. 213-218 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Oka,H.: "Constitutive activation of Mitogen-activated protein(MAP) kinases in human renal cell carcinoma." Cancer Res.55. 4182-4187 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Chatani,Y.: "Cell-type specific modulation of cell growth by TGF-β1 does not correlate with mitogen-activated protein kinase activation." J.Biol.Chem.270. 30686-30692 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hattori,A.: "Tumor necrosis factor(TNF) stimulates the production of nerve growth factor in fibroblasts via the 55-kDa type I TNF receptor." FEBS Lett.379. 157-160 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hattori,A.: "Bone morphogenetic protein-2 is markedly synergistic with tumor necrosis factor in stimulating the production of nerve growth factor in fibroblasts." Biochem.Mol.Biol.Int.(in press). (1996)

    • Related Report
      1995 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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