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Mechanism of IL-6 Gene Activation in Myeloma Cells

Research Project

Project/Area Number 01480300
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionHiroshima University

Principal Investigator

KAWANO Michio  Medical Hospital, Hiroshima Univ., Research Associate., 医学部・附属病院, 助手 (40161343)

Co-Investigator(Kenkyū-buntansha) KURAMOTO Atsushi  Research Institute for Nuclear Medicine and Biology, Hiroshima Univ., Professor, 原爆放射能医学研究所, 教授 (50034070)
FUJIMURA King  Research Institute for Nuclear Medicine and Biology, Hiroshima Univ., Associate, 原爆放射能医学研究所, 助教授 (80034114)
TANABE Osamu  Medical Hospital, Hiroshima Unv., Research Associate, 医学部・附属病院, 助手 (70221398)
Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1990: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1989: ¥3,400,000 (Direct Cost: ¥3,400,000)
KeywordsMyeloma cells / Interleukin-6 / Gene activation / Transcriptional factor / Nuclear factor / Autocrine growth / Multiple Myeloma / Interleukin 6 gene / Transcriptional Regulation / Nuclear binding protein / NF-IL-6 / Autocrine growth
Research Abstract

Human myeloma cells constitutively produce interleukin-6 (IL-6) and express IL-6 receptor, and an autocrine loop by IL-6 is operating in myeloma cells. Constitutive expression of IL-6 gene is considered to be closely associated with oncogenesis of myeloma. In order to confirm this, we investigated whether plasma cells in a pre-myeloma state, benign monoclonal gammopathy, produced IL-6 significantly. These plasma cells did not express any significant IL-6mRNA. This is suggestive that constitutive expression of IL-6 gene is characteristic of myeloma cells. We also established human myeloma cell lines and selected one myeloma cell line, KMS-5, which showed higher expression of IL-6mRNA. As for soluble factors modulating IL-6 gene expression, interleukin-1 (IL-1) was found to increase IL-6mRNA in myeloma cells, and interferon alpha and glucocorticoids decreased IL-6mRNA. We focused on the IL-1-induced IL-6 gene activation in myeloma cells. Transcriptional enhancer sequence concerning in IL-1-induced IL-6 gene activation has been identified as the palindrome sequence, ACATTGCACAATCT. NF-IL6 was identified to specifically bind to the IL-1-responsive element, and the gene encoding NF-IL6 has been cloned. We investigated the relationship between IL-6 and NF-IL6 expression in myeloma cells by RT-PCR and Northern blotting, and NF-IL6 expression were detected in all myeloma cells. On the other hand, there were not any structural alterations of IL-6 gene in myeloma cells by Southern blotting. Taken together, we consider that constitutive expression of IL-6 gene in human myeloma cells may be due to the altered expression of its transcriptional factor, NF-IL6. Further investigation on the mechanism of IL-6 gene activation is now in progress ; 1) the effect of induction of anti-sense NF-IL6 on IL-6 gene expression, and 2) identification of other transcriptional factors.

Report

(3 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Michio KAWANO: "Cytokines as autocrine growth factors in malignancies." Cancer Surveys. 8. 905-919 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Michio KAWANO: "Interleukinー1 accelerates autocrine growth of myeloma cells through interleukinー6 in human myeloma." Blood. 73. 2145-2148 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Osamu TANABE: "BSFー2/ILー6 does not augment Ig secretion but stimulates proliferation in myeloma cells." American Journal of Haematology. 31. 258-262 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hideo TANAKA: "Sensitive inhibitory effect of interferonーalpha on Mーprotein secretion of human myeloma cells." Blood. 74. 1718-1722 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Itsuo YAMAMOTO: "Production of interleukin 1,a potent bone resorbing cytokine,by cultured human myeloma cells." Cancer Research. 49. 4242-4246 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hideaki ISHIKAWA: "Effect of glucocorticoids on the biologic activities of myeloma cells." Blood. 75. 715-720 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kawano, M., Kuramoto, A., Hirano, T., Kishimoto, T.: "Cytokines as autocrine growth factors in malignancies." Cancer Survey. 8. 905-919 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kawano, M., Yamamoto, I., Iwant, K., Tanaka, H., Asaoku, H., Tanabe, O., Ishikawa, H., Nobuyoshi, M., Ohmoto, Y., Hirai, Y., Kuramoto, A.: "Interleukin-1 beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma." Blood. 73. 1646-1649 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kawano, M., Tanaka, H., Ishikawa, H., Nobuyoshi, M., Iwato, K., Asaoku, H., Tanabe, O., Kuramoto, A.: "Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma." Blood. 73. 2145-2148 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tanabe, O., Kawano, M., Tanaka, H., Iwato, K., Asaoku, H., Ishikawa, H., Nobuyoshi, M., Hirano, T., Kishimoto, T., Kuramoto, A.: "BSF-2/IL-6 dose not augment Ig secretion but stimulates proliferation in myeloma cells" Am. J. Hematol. 31. 258-262 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tanaka, H., Tanabe, O., Iwato, K., Asaoku, H., Ishikawa, H., Nobuyoshi, M., Kawano, M., Kuramoto, A.: "Sensitive inhibitory effect of Interferon-alpha on M-protein secretion of human myeloma cells." Blood. 74. 1718-1722 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kawano, M., Iwato, K., Asaoku, H., Tanabe, O., Tanaka, H., Ishikawa, H., Kuramoto, A.: "Altered cytokine activities are related to the suppression of synthesis of normal immunoglobulin in multiple myeloma." Am. J. Hematol. 30. 91-96 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hirano, T., Taga, T., Yamasaki, K., Matsuda, T., Suematsu, S., Tang, B., Hirata, Y,. Yawata, H., Hibi, M., Natsuka, S., Akira, S., Yoshizaki, K., Kawano, M., Yamamura, K., Kishimoto, T.: "Interleukin 6 and its receptor" Recent Progress in Cytokine Research [The First International Mochida Memorial Symposium 1988]. 265-285 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hirano, T., Taga, T., Yamasaki, K., Matsuda, T., Tang, B., Suematsu, S., Horii, Y., Hirata, Y., Yawata, H., Muraguchi, A., Kawano, M., Miyasaka, N., Shimizu, M., Kishimoto, T.: "Interleukin 6 and its receptor : Pathological role in autoimmunity and lymphoid malignancy" Advances in Immunopharmacology 4 (eds. by Hadden, J. W., Spreafico, F., Yamamura, Y., Austen, K. F., Dukor, P., Masek, K.). 161-168 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hirano, T., Taga, T., Yamasaki, K., Matsuda, T., Tang, B., Muraguchi, A., Horii, Y., Suematsu, S., Hirata, Y., Yawata, H., Shimizu, M., Kawano, M., Kishimoto, T.: "A multifunctional cytokine (IL-6/BSF-2) and its receptor" Int. Arch. Allergy Appl. Immunol. 88. 29-33 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Matsuda, T., Suematsu, S., Kawano, M., Yoshizaki, K., Tang, B., Tanabe, O., Nakajuma, T., Akira, S., Hirano, T., Kishimoto, T.: "IL-6/BSF2 in normal and abnormal regulation of immune responses" Annals of the New York Academy of Sciences [Regulation of the acute phase and immune responses : Interleukin-6] (eds. by Sehgal, P. B., Grieninger, G., Tasato, G.). 557. 466-477 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kishimoto, T., Taga, T., Yamasaki, K., Matsuda, T., Tang, B., Muraguchi, A., Horii, Y., Suematsu, S., Hirata, Y., Yawata, H., Shimizu, M., Kawano, M., Hirano, T.: "Normal and abnormal regulation of human B cell differentiation by a new cytokine, BSF2/IL-6." Mechanisms of Lymphocyte Activation and Immune Regulation II (eds by Sudhir Gupta and William E. Paul). 135-143 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yamamoto, I., Kawano, M., Sone, T., Iwato, K., Tanaka, H., Ishikawa, H., Kitamura, N., Lee, K., Shigeno, C., Konishi, J., Asaoku, H., Tanabe, O., Nobuyoshi, M., Ohmoto, Y., Hirai, Y., Higuchi, M., Ohsawa, T., Kuramoto, A.: "Production of interleukin 1beta, a potent bone resorbing cytokine, by cultured human myeloma cells" Cancer Res. 49. 4242-4246 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kawano, M., Iwato, K., Asaoku, H., Tanabe, O., Tanaka, H., Ishikawa, H., Imamura, N., Kuramoto, A.: "Heterogeneous response of B cell Chronic Lymphocytic Leukaemia (B-CLL) cells to anti-human IgM antibody (anti-mu) and B cell Stimulatory Factor l (BSF-1)" Brit. J. Haematol. 71. 47-51 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Ishikawa, H., Tanaka, H., Iwato, K., Tanabe, O., Asaoku, H., Nobuyoshi, M., Yamamoto, I., Kawano, M., Kuramoto, A.: "Effect of glucocorticoids on the biologic activities of myeloma cells : Inhibition of interleukin-1beta osteoclast activating factor-induced bone resorption" Blood. 75. 715-720 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yamamoto, I., Kawano, M., Sone, T., Iwato, K., Tanaka, H., Ishikawa, H., Kitamura, N., Lee, K., Shigeno, C., Asaoku, H., Tanabe, O., Nobuyoshi, M., Konishi, J., Kuramoto, A.: "Production of interleukin 1beta, a potent bone resorbing cytokine, by cultured human myeloma cells" Calcium Regulation and Bone Metabolism (eds. D. V. Cohn, F. H. Glorieux, T. J. Martin). 330-335 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Nobuyoshi, M., Kawano, M., Tanaka, H., Ishikawa, H., Tanabe, O., Iwano, K., Asaoku, H., Sakai, A., Kuramoto, A.: "Increased expression of the c-myc gene may be related to the aggressive transformation of human myeloma cells." Brit. J. Haematol. 77. 397-402 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Hideaki ISHIKAWA: "Effects of glucocorticoids on the biologic activities of myeloma cells." Blood. 75. 715-720 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Masaharu NOBUYOSHI: "Increased expression of the cーmyc gene may be related to the aggressive transformation of human myeloma cells." British journal of Haematology. 77. 397-402 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 河野 道生: "被爆者における多発性骨髄腫の細胞生物学的研究 2.cーmgc遺伝子活性化と骨髄腫進展との関連について" 広島医学. 43. 410-413 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 田邉 修: "ILー6と造血幹細胞" 造血因子. 1. 62-68 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 坂井 晃: "インタ-ロイキン6と骨髄腫,骨髄腫細胞から産生されるILー6" Mebio. 7. 50-54 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 河野 道生: "Annual Review血液1990" 中外医学社, 216 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Michio KAWANO: "Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma." Blood. 73. 2145-2148 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Hideo TANAKA: "Sensitive inhibitory effect of interferon-alpha on M-protein secretion of human myeloma cells." Blood. 74. 1718-1722 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Osamu TANABE: "BSF-2/IL-6 does not augment Ig secretion but stimulates proliferation in myeloma cells." American Journal of Hematology. 31. 258-262 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Hideaki ISHIKAWA: "Effect of glucocorticoids on the biologic activities of myeloma cells." Blood. 75. 715-720 (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Michio KAWANO: "Cytokines as autocrine growth factors in malignancies." Cancer Surveys. 8. (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 河野道生: "多発性骨髄腫とILー6" 実験医学. 7. 55-60 (1989)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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