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1999 Fiscal Year Final Research Report Summary

Pathophyiological and immunopharmacological studies on chemokines and their receptors

Research Project

Project/Area Number 10044254
Research Category

Grant-in-Aid for Scientific Research (A).

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionKanazawa University

Principal Investigator

MUKAIDA Naofumi  Cancer Research Institute, Kanazawa University Professor, がん研究所, 教授 (30182067)

Co-Investigator(Kenkyū-buntansha) AKIYAMA Mariko  Cancer Research Institute, Kanazawa University Research Associate, がん研究所, 助手 (60019867)
KASAHARA Tadashi  Kyoritu Pharmaceutical College Professor, 薬学部, 教授 (60049096)
Project Period (FY) 1998 – 1999
KeywordsInterleukin-8 (IL-8) / monocyte chemoattractant protein-1 (MCP-1) / neutrophil / macrophage / macrophage inflammatory protein (MIP)-1α / angiogenesis / interferon (INF)-γ / renal diseases
Research Abstract

This study was performed to clarify the pathophysiological roles of chemokines and their receptors in various types of diseases. Through these studies, we obtained the results as follows.
1) Macrophage inflammatory protein (MIP)-2, a functional homologue of human interleukin-8 (IL-8), was produced periodically at mouse vaginal epithelium immediately after the ovulation. Moreover, locally produced MIP-2 was involved in postovulatory neutrophil migration into vagina.
2) Subcutaneous injection of monocrotaline into rats caused chronic pulmonary hypertension accompanied with intrapulmonary macrophage infiltration. Monocyte chemoattractant protein (MCP)-1 was produced at the onset of macrophage infiltration. The administration of anti-MCP-1 antibodies reduced macrophage infiltration and alleviated pulmonary hypertension. These results suggest that MCP-1 was involved in the pathogenesis of monocrotaline-induced pulmonary hypertension, through inducing macrophage infiltration.
3) In an acute typ … More e of IgA nephropathy, urinary IL-8 levels were increased with no increase in urinary MCP-1 levels. In contrast, in a chronic type of IgA nephropathy which is prone to develop chronic renal failure, urinary MCP-1 levels were markedly increased while urinary IL-8 levels were not. Moreover, we found that urinary MIP-lα and MCP-1 levels correlated with crescent formation and interstitial lesions in chronic crescentic glomerulonephritis, respectively. Thus, various chemokines were produced locally and differentially at the diseased kidney, thereby contributing to the establishment of various renal lesions.
4) Angiogenesis and tumor formation was enhanced by IL-8 cDNA transfection into gastric cancer cell lines. Moreover, we observed IL-8 mRNA and protein expression near necrotic areas in the tumor sites. Because the area close to necrosis is presumed to be hypoxic, we rendered human ovarian cancer and melanoma cell lines hypoxia. Hypoxia activated two types of transcription factors, AP-1 and NF-ィイD2KィエD2B, thereby inducing IL-8 production. Furthermore, we obtained definitive evidence on the presence of IL-8 receptors on human gastric cancer cells. Collectively, these results suggest that IL-8 may be involved in tumor progression by inducing angiogenesis and changing the phenotypes of cancer cells.
5) We observed that C5a activated AP-1 and NF-ィイD2KィエD2B, thereby inducing IL-8 production in a human monocyte cell line.
6) We obtained the evidence that interferon-γ was involved in granuloma formation in Propinibacterium acnes-primed mice and subsequent lipopolysaccharide-induced liver tissue damage, by regulating macrophage infiltration and the production of several cytokines including tumor necrosis factor (TNF)-α IL-12, and IL-18. Less

  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Sonoda, Y., Mukaida, N., Wang, J. B., Kasahara, T., et al.: "Physiologic regulation of postovulatory neutrophil migration into vagina by a C-X-C chemokine(s)"Journal of Immunology. 160. 6159-6165 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yokoyama, H., Wada, T., Furuichi, K., Segawa, C., Mukaida, N., et al.: "Urinary levels of chemokines (MCAF and IL-8) reflect distinct disease activities and phases of IgA nephropathy"Journal of Leukocyte Biology. 63. 493-499 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mukaida, N., Harada, A., and Matsushima, K.: "Interleukin-8 and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions (Invited review)"Cytokine and Growth Factor Reviews. 9. 9-23 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuji, K., Mukaida, N., Harada, A., Kaneko, S., Matsushita, E., et al.: "Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-γ-deficient mice by a concomitant reduction of TNF-α, IL-12 and IL-18 production"Journal of Immunology. 162. 1049-1055 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Xu, L. Xie, K., Mukaida, N., Matsushima, K., and Fidler, I. J.: "Hypoxia-induced elevation in interleukin-8 expression by human ovarian cancer carcinoma cells"Cancer Research. 59. 5822-5829 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hsu, M. H., Wang, M., Browning, D. D., Mukaida, N. and Ye, R. D.: "NF-_κB activation is required for C5a-induced IL-8 gene expression in mononuclear cells"Blood. 93. 3241-3249 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mukaida, N., Wang, J.-b., and Matsushima, K.: "CDw128 Workshop Panel : Human Interleukin-8 (IL-8) Receptors. In Leukocyte Typing IV"Garland Press. 840-843 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mukaida, N., and Matsushima, K.: "Interleukin-8 and its receptor. In Encyclopedia of Immunology"Academic Press. 1466-1471 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sonoda, Y., Mukaida, N., Wang, J. -b., Shimada-Hiratsuka, M., Naito, M., Kasahara, T., Harada, A., Inoue, M., Matsushima, K.: "Physiologic regulation of postovulatory neutrophil migration into vagina by a C-X-C chemokine(s)."Journal of Immunology. 160. 6159-6165 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yokoyama, H., Wada, H., Furuichi, K., Segawa, C., Hisada, Y., Ohta, S., Kobayashi, K. -I., Su, S. -b., Mukaida, N., Matsushima, K.: "Urinary levels of chemokines (MCAF and IL-8) reflect distinct disease activities and phases of IgA nephropathy"Journal of Leukocyte Biology. 63. 493-499 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kimura, H., Kasahara, Y., Kurosu, K., Sugito, K., Takiguchi, Y., Terai, M., Mikata, A., Natsume, M., Mukaida, N., Matsushima, K., Kuriyama, T.: "Attenuation of monocrotaline-induced pulmonary hypertension by antibodies to a monocyte chemotactic and activating factor, MCAF/MCP-1."Laboratory Investigation. 78. 571-581 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mukaida, N., Harada, A., Matsushima, K.: "Interleukin-8 and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions."Cytokine & Growth Factor Reviews. 9. 9-23 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuji, H., Mukaida, N., Harada, A., Kaneko, S., Matsushita, E., Nakanuma, Y., Tsutsui, H., Okamura, H., Nakanishi, K., Tagawa, Y., Iwakura, Y., Kobayashi, K., Matsushima, K.: "Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-γ-deficient mice by a concomitant reduction of TNF-α, IL-12, and IL-18 production."Journal of Immunology. 162. 1049-1055 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hsu, M. H., Wang, M., Browining, D. D., Mukaida, N., Ye, R. D: "NF-κB activation is required for C5a-induced IL-8 gene expression in mononuclear cells."Blood. 93. 3241-3249 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masamune, A., Shimosegawa, T., Masamune, O., Mukaida, N., Koizumi, M, Toyota, T.: "Helicobacter pylori-dependent ceramide production may mediate increased interleukin 8 expression in human gastric cancer cell lines."Gastroenterology. 116. 1330-1341 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitadai, Y., Takahashi, Y., Haruma, K., Naka, K., Sumii, K., Yokozaki, H., Yasui, W., Ohmoto, Y., Mukaida, N., Kajiyama, G., Fidler, I. J., Tahara, E.: "Transfection of interleukin-8-increases angiogenesis and tumorigenicity of human gastric carcinoma cells in nude mice."British Journal of Cancer. 81. 647-653 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Xu, L., Xie, K., Mukaida, N., Matsushima, K., Fidler, I. J.: "Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells."Cancer Research. 59. 5822-5829 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Wada, T., Furuichi, K., Segawa, C., Shimizu, M., Sakai, N., Takeda, S. -I., Takasawa, K., Kida, H., Kobayashi, K. -I., Mukaida, N., Ohmoto, Y., Matsushima, K., Yokoyama, H.: "MIP-1α and MCP-1 contribute to crescents and interstitial lesions via the cognate chemokine receptor in human crescentic glomerulonephritis."Kidney International. 56. 995-1003 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kunz, M., Hartmann, A., Flory, E., Toksoy, A., Koczan, D., Thiesen, H. -J., Muakida, N., Neumann, M., Rapp, U. R., Broeker, E. -B., Gillitzer, R.: "Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness."American Journal of Pathology. 115. 753-763 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mukaida, N., Wang, J. -b., Matsushima, K.: "CDw128 Workshop Panel : Human interleukin-8 (IL-8) receptors."Leukocyte Typing IV, Garland Press. 840-843 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mukaida, N. Matsushima, K.: "Interleukin 8 and its receptor"Encyclopedia of Immunology, IInd Ed., Academic Press. 1466-1471 (1998)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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