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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)
JOOST J. Oppenheim  米国, 国立・癌研究所, 研究室主任
CHRISTIAN G. Larsen  デンマーク王国, 国立・Aarhus大学・医学部, 助教授
LARSEN Chris  デンマーク王国国立Aarhus大学, 医学部, 助教授
OPPENHEIM Jo  米国国立癌研究所, 研究室主任
西堀 宗樹  金沢大学, がん研究所, 非常勤研究員
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1999: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1998: ¥4,600,000 (Direct Cost: ¥4,600,000)
KeywordsInterleukin-8 (IL-8) / monocyte chemoattractant protein-1 (MCP-1) / neutrophil / macrophage / macrophage inflammatory protein (MIP)-1α / angiogenesis / interferon (INF)-γ / renal diseases / NF-κB / AP-1 / MCP-1 / エオタキシン / ケモカイン / 転移 / MIP-2 / IL-8 / IL-10
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

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kunz, M., Hartmann, A., Flory, E., Toksoy, A., Koczan, D., Thiesen, H.J., Mukaida, N., Neumann, M., Rapp, U et al.: "Anoxia-induced up-regulation of Interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness."American Journal of Pathology. 155(3). 753-763 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tsuji, H., Mukaida, N., Harada, A., Kaneko, S., Matsushita, E., Nakanuma, Y., Tsutsui, H. et al.: "Alleviation of lipopolysaccharide-induced 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hsu, M.H., Wang, M., Browning, D.D., Mukaida, N. and Ye, R.D.: "NF-κB activation is required for C5a-induced interleukin-8 gene expression in mononuclear cells"Blood. 93(10). 3241-3249 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Wada, T., Furuichi, K, Segawa, C., Shimizu, M., Sakai, N., Takeda, S-i., Takasawa, K., Kida, H., Kobayashi, K-i, Mukaida, N. et al.: "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)

    • Related Report
      1999 Annual Research Report
  • [Publications] Natsume, M., Tsuji, H., Haruda, A., Akiyama, M., Yano, T., Ishikura, H., Nakanishi, I., Mukaida, N. et al.: "Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice"Journal of Leukocyte Biology. 66(10). 601-608 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 向田 直史: "免疫系(標準薬理学第6版)"医学書院. (印刷)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sonoda,Y.,et al.: "Physiologic regulation of postovulatory neutrophil migration into vagina by a C-X-C chemokine(s)." J.Immunol.160. 6159-6165 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mukaida,N.,et.al.: "Interleukin-8 and monocyte chemotactic and activating factor(MCAF/MCP-1),chemokines essentially involved in inflammatory and immune reactions." Cytokine Growth factor Rev.9. 9-23 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yokoyama,H.,et.al.: "Urinary levels of chemokines(MCAF and IL-8)reflect distinct disease activities and phases of IgA nephropathy." J.Leukocyte Biol.63. 493-499 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mori,N.,et.al,: "Human T-cell leukemia virus type I Tax transactivates human interleukin 8 gene through acting concurrently on AP-1 and NF-_kB-like sites." Cancer Res.58. 3993-4000 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Asagoe,K.,et.al.: "Dewnregulation of CXCR2 expression on human polymorphonuclear leukocytes by TNF-α." J.Immunol.160. 4518-4525 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kimura,H.,et.al.: "Attenuation of monocrotaline-induced pulmonary hypertension by antibodies to a monocyte chemotactic and activating factor,MCAF/MCP-1." Lab.Invest.78. 571-581 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mukaida,N.and Matsushima,K.: "interleukin 8 and its receptor." Academic Press,London,United Kingdom, 6 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mukaida,N.,et.al.: "CDw128 Workshop Panel:Human interleukin-8(IL-8)" Garland press,New York.USA, 3 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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