| Project/Area Number |
13670513
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
KIYOHARA Tatsuya Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (50322178)
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| 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)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| 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)
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| Keywords | Conh's disease / macrophage / mice / IL-10 / lipopolysaccharide / CD40 / TNFα / IL-12 |
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| 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.
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