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Development of a new therapy of Chohn's disease by the regulation of Macrophage/Monocyte function

Research Project

Project/Area Number 13670513
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionOsaka University

Principal Investigator

KIYOHARA Tatsuya  Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (50322178)

Co-Investigator(Kenkyū-buntansha) MURAYAMA Yoko  Osaka University Hospital, Medical Staff, 医学部附属病院, 医員(臨床研究)
MIYAZAKI Yoshiji  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30303960)
SHINOMURA Yasuhisa  Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90162619)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsConh's disease / macrophage / mice / IL-10 / lipopolysaccharide / CD40 / TNFα / IL-12
Research Abstract

The present research was designed to elucidate the role of macrophages in the pathogenesis of inflammatory bowel disease and to develop new therapy. At first, proinflammatory characteristics of macrophages were estimated in a murine model of spontaneous intestinal inflammation. Peritoneal macrophages from IL-10 deficient mice were stimulated with lipopolysaccharide (LPS) or an anti-CD40 nonoclonal antibody (mAb). Cytokine release was assessed by enzyme-linked immunosorbent assay. In the presence of LPS or anti-CD40 mAb, TNF-alpha and IL-12p70 release from macrophages of mutant mice was significantly higher than that from macrophages of wild-type mice. This may be due to the difference in IL-10 production by macrophages, since activated macrophages of wild-type mice produced IL-10 in amounts sufficient to suppress an increased release of cytokines from activated macrophages of mutant mice. CD40 expression was examined by two-color flow cytometric analysis. In mutant mice, the percent of CD40-postive macrophage and their mean fluorescence intensity were essentially the same as those in wild-type mice. Induction of suppressor of cytokine signaling 3 (SOCS3) mRNA was evaluated by real-time quantitative RT-PCR. LPS and CD40 stimulation induced significantly high level of SOCS3 expression in macrophages of mutant mice in comparison to those of wild-type mice. Thus, macrophages from a murine model of inflammatory bowel disease demonstrated enhanced responsiveness to immunological and bacterial stimuli. This suggests significant roles of macrophages in the pathogenesis of inflammatory bowel disease.
Then, we have examined whether the inhibition of macrophage activation may reduce disease activity of colitis, or not. Treatment of mutant mice by anti-CD40 antibody did not ameliorate their colitis. On the other hand, LPS antagonist (E5564) improved disease activity of mice colitis. LPS antagonist may be a candidate of a new therapeutic agent for Cronh's disease.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] T.Kiyohara et al.: "A decreased number of c-kit-expressing cells in a patient with afferent loop syndrome"J Gastroenterol.. 38巻4号(in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] R.Takakura et al.: "Enhanced macrophage responsiveness to lipopolysaccharide and CD40 stimulation in a murine model of inflammatory bowel disease : IL-10-deficient mice"Inflammation Research. 51巻8号. 409-415 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Nakahara: "Deficiency of KIT-positive cells in the colon of patients with diabetes mellitus"J. Gastroenterol. Hepatol.. 17巻20号. 666-670 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Mutayama et al.: "Significance of the association between heparin-binding epidermal growth factor-like growth factor and CD9 in human gastric cancer"Int. J. Cancer.. 98巻4号. 505-513 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Toyota et al.: "Peroxysome proliferator-activated receptor g reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1"Life Sciences. 70巻13号. 1565-1575 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Ichiba et al.: "Epidermal growth factor inhibits the growth of TE8 esophageal cancer cells through the activation of STAT1"J. Gastroenterol.. 37巻7号. 497-503 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kiyohara T, Shinomura Y, Isozaki K, Nakahara M, Tsutsui S. Nishibayashi N, Miyazaki Y, Miyagawa JI, Matsuzawa Y.: "A decreased number of c-kit-expressing cells in a patient with afferent loop syndrome"J Gastroenterol.. 38(4), (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Toyota M, Miyazaki Y, Kitamura S. Nagasawa Y, Kiyohara T, Shinomura Y, Matsuzawa Y.: "Peroxysome proliferator-activated receptor γ reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1"Life Sciences. 70. 1565-1575 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takakura R, Kiyohara T. Murayama Y, Miyazaki Y, Miyoshi Y, Shinomura Y, Matsuzawa Y.: "Enhanced macrophage responsiveness to lipopolysaccharide and CD40 stimulation in a murine model of inflammatory bowel disease: IL-10-deficient mice"Inflammation Research. 51(8). 409-415 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ichiba M, Miyazaki Y. Kitamura S, Kiyohara T, Schinomura Y, Matsuzawa Y.: "Epidermal growth factor inhibits the growth of TE8 esophageal cancer cells through the activation of STATI"J Gastroenterol.. 37(7). 497-503 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Murayama Y, Miyagawa J, Shinomura Y, Kanayama S. Isozaki K, Yamamori K, Mizuno H, Ishiguro S, Kiyohara T, Miyazaki Y, Taniguchi N, Higashiyama S, Matsuzawa Y.: "Significance of the association between heparin-binding epidermal growth factor-like growth factor and CD9 in human gastric cancer"Int J Cancer. 98(4). 505-513 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakahara M, Isozaki K, Hirota S, Vanderwinden JM, Takakura R, Kinoshita K, Miyagawa J, Chen H, Miyazaki Y, Kiyohara T, Shinomura Y, Matsuzawa Y.: "Deficiency of KIT-positive cells in the colon of patients with diabetes mellitus"J Gastroenterol Hepatol.. 17(6). 666-670 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T.Kiyohara et al.: "A decreased number of c-kit-expressing cells in a patient with afferent loop syndrome"J Gastroenterol. 38(4)(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] R.Takakura et al.: "Enhanced macrophage responsiveness to lipopolysaccharide and CD40 stimulation in a murine model of inflammatory bowel disease : IL-10-deficient mice"Inflammation Research. 51(8). 409-415 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Nakahara: "Deficiency of KIT-positive cells in the colon of patients with diabetes mellitus"J.Gastroenterol.Hepatol.. 17(6). 666-670 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Mutayama et al.: "Significance of the association between heparin-binding epidermal growth factor-like growth factor and CD9 in human gastric cancer"Int.J.Cancer. 98(4). 505-513 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Toyota et al.: "Peroxysome proliferator-activated receptor g reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1"Life Sciences. 70(13). 1565-1575 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Ichiba et al.: "Epidermal growth factor inhibits the growth of TE8 esophageal cancer cells through the activation of STAT1"J.Gastroenterol. 37(7). 497-503 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Toyota et al.: "Peroxisome proliferator-activated receptor γ reduces the growth rate of pancreatic cencer cells though the reduction of cyclin D1"Life Sci. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Ueyama et al.: "Impaired sensitivity to Fas-induced apoptosis of lymphocytes in ulcerative colitis lesions"Trends in Gastroenterology and Hepatology(H. Asakura, Y. Aoyagi, S. Nakazawa Eds). 47-52 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Hiraoka, et al.: "Gastrin induces CXC chemokine expression in gastric epithelial cells though activation of NF-kappaB"Am J Physiol. 281(3). G735-G742 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Kitamura, et al.: "PPARγ agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells"Int. J. Cancer. 94(3). 335-342 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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