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Development of assay systems for chemokines and their receptors and establishment of their diagnostic value

Research Project

Project/Area Number 10557249
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Laboratory medicine
Research InstitutionKanazawa University

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) 秋山 万里子 (秋山 萬里子)  金沢大学, がん研究所, 助手 (60019867)
Project Period (FY) 1998 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1999: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥5,300,000 (Direct Cost: ¥5,300,000)
Keywordsinterleukin-8 (IL-8) / MGP-1 / angiogenesis / hypoxia / MIP-lα / hepatitis C virus / CCR1 / NF-_kB / C型肝炎ウィルス / NS5A蛋白 / PPAR-γ / 骨髄前駆細胞 / 臍帯血 / 単球走化因子(MCP-1) / 肝癌 / インターロイキン4 / サイトメガロウイルス / CCR5 / NF-_κB / AP-1 / MCP-1 / エオタキシン / 腎疾患 / ケモカイン / レセプター / MIP-2 / IL-8 / マクロファージ / 遺伝子転写 / Tax
Research Abstract

1) A functional interleukin-8 (IL-8) homologue, macrophage inflammatory protein (MIP)-2, was produced by mouse vaginal epithelium, periodically after ovulation and caused neutrophil infiltration into vaginal epithelium.
2) In acute type of IgA nephropathy, urinary IL-8 levels were increased with undetectable urinary monocyte chemoattractant protein (MCP)-1. In contrast, MCP-1 but not IL-8 levels were increased in urines from chronic type of IgA nephropathy patients. Moreover, crescentic glomerulonephritis, MIP-lα and MCP-1 produced in the kidney, were responsible for crescent formation and interstitial lesions, respectively. Furthermore, in diabetic nephropathy, macrophages in interstitium were positive for MCP-1 and urinary MCP-1 levels were increased.
3) IL-8 protein and mRNA were detected near necrotic areas inside tumor tissues, where oxygen content is presumed to be low. The exposure of several types of cell lines to hypoxia activated two transcription factors, NF-_kB and AP-1, and eventually induced IL-8 gene transcription. Human gastric cancer cell lines transfected with IL-8 gene exhibited faster tumor formation with enhanced angiogenesis when injected into nude mice, compared with parental cells. Moreover, most of gastric cancer cell lines expressed IL-8 receptors and IL-8 induced the expression of metastasis-related genes in some gastric cancer cell lines.
4) In hepatoma cell lines, two distinct transcription factors, PEA3 and AP-1, were constitutively activated, which resulted in constitutive IL-8 gene transcription. Among patients infected with human hepatitis C virus, serum IL-8 levels were increased in patients suffering from hepatoma, when compared with chronic hepatits and liver cirrhosis patients. Moreover, the transduction of nonstructural protein (NS) 5A of human hepatitis C virus induced IL-8 gene transcription as well as IL-8 protein secretion.
5) In cord blood, CCR1 expression among CD34-positive cells, was restricted to erythroid progenitor cells.

Report

(5 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (42 results)

All Other

All Publications (42 results)

  • [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-XC 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
      2001 Final Research Report Summary
  • [Publications] Wada, T., Furuichi, K., Segawa, C., Shimizu, M., Sakai, N., Takeda, S., Takasawa, K., Kido, H., Kobayashi, K., 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(和文)」より
    • Related Report
      2001 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 cancer carcinoma cells"Cancer Res.. 59. 5822-5829 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Iguchi, A., Kitajima, I., Yamakuchi, M., Ueno, S., Aikou, T., Kubo, T., Matsushima, K., Mukaida, N., Maruyama, I.: "PEA3 and AP-1 are required for constitutive IL-8 gene expression in hepatoma cells"Biochem. Biophys, Res. Commun.. 279. 166-171 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Polyak, S.J., Khabar, K.S.A., Paschal, D.M., Ezelle, H.J., Duverlei, G., Barber, G.N., Levy, D.E., Mukaida, N., Gretch, D.R.: "Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading, to partial inhibition of the interferon-induced antiviral response"Journal of Virology. 75. 6095-6106 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] de Wynter, E.A., Heyworth, C.M., Mukaida, N., Jaworska, E., Weffort-Santos, A., Matsushima, K., Testa, N.G.: "CCR1 chemokine receptor expression isolates erythroid from granulocyte-macrophage progenitors"Journal of Leukocyte Biology. 70. 455-460 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 向田 直史: "標準薬理学(第6版)"医学書院. 15/477 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 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 Immmunology. 160. 6159-6165 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wada, T., Furuichi, K, Segawa, G, Shimizu, M., Sakai, N., Takeda, S.I., Takasawa, K, Kida, H., Kobayashi, K.-I., Mukaida. N. Ohmoto, Y., Matsushima, K, and Yokoyama, H: "MIP-1αand 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
      2001 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(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Iguchi, A., Kitajima, L, Yamakuchi, M., Ueno, S., Aikou, T., Kubo, T., Matsushima, K, Mukaida. N., Maruyama, I: "PEA3 and AP-1 are required for constitutive IL-8 gene expression in hepatoma cells"Biochemical and Biophysical Research Communication. 279. 166-171 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Polyak,S. J., Khabar, K.SA, Paschal, D.M., Ezelle, H.J., Duverlei, G., Barber, G.N., Levy, D.E., Mukaida. N., Gretch, DH.: "Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response"Journal of Virology. 75. 6095-6106 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] de Wynter, E.A., Heyworth, CM., Mukaida. N. Jaworska, E., Weffort-Santos, A., Matsushima, K, Testa, N.G: "CCRl chemokine receptor expression isolates erythroid from granulocyte-macrophage progenitors"Journal of Leukocyte Biology. 70. 455-460 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Polyak, S. J., Khabar, K.S. A., paschal, D, M., Ezelle, H. J., Duverlei, G., Barber, G. N., Levy, D. E., Mukaida, N., Gretch D. R.: "Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral responce"Journal of Virology. vol.75. 6095-6106 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Zhang, X., Wang, J.M., Gong, W.H., Mukaida, N., Young, H. A.: "Differential regulation of chemokine gene expression by 15-deoxy-Δ^<12,14> prostaglandin J_2"Journal of Immunology. vol.166. 7104-7111 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Smith, R.S., Fedyk, E. R., Springer, T. A., Mukaida, N., Iglewski, B. H., Phipps, R. P: "IL-8 production in human lung fibroblasts and epithelial cells activated by the Pseudomonas autoinducer N-3-oxododecanoyl homoserine lactone is transcriptionally regulated by NF-κB and activator protein-2"Journal of Immunology. vol.167. 366-374 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] de Wynter, E.A., Heyworth, C. M., Mukaida N., Jaworska, E., Weffort-Santos, A., Matsushima, K., Testa, N. G.: "CCR1 chemokine recepter expression isolates erythroid from granulocyte-macrophage progentiors"Journal of LeuKocyte Biology. vol.70. 455-460 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wada, T., Furuichi, K., Sakai, N., Hisada, Y., Kobayashi, K., Mukaida, N., Tomosugi, N., Matsushima. K., Yokoyama, H.: "Involvement of p38 mitogen-activated protein kinase followed by chemokine expression in crescentic glomerulonephritis"American Journal of Kidney Diseases. vol.38. 1169-1177 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kitamura, K., Nakamoto Y., Akiyama, M., Fuji, C., Kondo, T., Kobayashi, K., Kaneko, S., Mukaida, N.: "Pathogenic roles of tumor necrosis factor receptor p55-mediated signals in dimethylnitrosamine-induced murine liver fibrosis"Laboratory Investigation. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 向田 直史: "標準薬理学(第6版)"医学書院. 15/477 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mukaida,N.: "Interleukin-8 : an expanding universe beyond neutrophil chemotaxis and activation."International Journal of Hematology. 72. 391-398 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nokihara,H.,Yanagawa,H.,Nishioka,Y.,Yano,S.,Mukaida,N.,Matsushima,K.,and Sone,S.: "Natural killer cell-dependent suppression of systemic spread of human lung adenocarcinoma cells by monocyte chemoattractant protein-1 gene transfection in severe combined immunodeficient mice."Cancer Research. 60. 7002-7007 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Iguchi,A.,Kitajima,I.,Yamakuchi,M.,Ueno,S.,Aikou,T.,Kubo,T.,Matsushima,K.,Mukaida,N.,and Maruyama,I.: "PEA3 and AP-1 are required for constitutive IL-8 gene expression in hepatoma cells."Biochemical Biophysical Research Communication. 279. 161-171 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Murayama,T.,Mukaida,N.,Sadanari,H.,Yamaguchi,N.,Khabar,K.S.,Tanaka,J.,Matsushima,K.,Mori,S.,& Eizuru,Y.: "The immediate early gene 1 product of human cytomegalovirus is sufficient for up-regulation of interleukin-8 gene expression."Biochemical Biophysical Research Communication. 279. 298-304 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kitadai,Y.,Haruma,K.,Mukaida,N.,Ohmoot,Y.,Matsutani,N.,Yasui,W.,Yamamoto,S.,Sumii,K.,Kajiyama,G.,Fidler,I.J.,and Tahara,E.: "Regulation of disease-progression genes in human gastric carcinoma cells by interleukin 8"Clinical Cancer Research. 6. 2735-2740 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishihori,H.,Tsuji,H.,Wang,H.,Tahara,H.,Akiyama,M.,Ogawa,Y.,Matsushima,K.,Iwakura,Y.,and Mukaida,N.: "Participation of endogenously produced interferon γ in interleukin-4-mediated tumor rejection."Human Gene Therapy. 11. 659-668 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Khabar,K.S.A.,Murayama,T.,al-Ahdal,M.N.,Mukaida.N.,and Matsushima,K.: "Advances in Animal Virology (Jameel,S.,and Villarreal, L.eds.)"Science Publisher Inc.. 323-335 (2000)

    • Related Report
      2000 Annual Research Report
  • [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 malanoma. A potential mechanism for high tumor aggressiveness."Amerian 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., Tsutsuji, 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."Kindney International. 56. 995-1003 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Wada, T., Furuichi, K, Sakai, N., Shimizu, M., Segawa, C., Kobayashi, K., Mukaida, N., Kasahara, T., et al.: "Eotaxin contributes to renal interstitial eosinophilia."Nephrology Dialysis Transplantation. 14. 76-80 (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.: "Downregulation 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)receptors." 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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