| Project/Area Number |
13670461
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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 |
内科学一般
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| Research Institution | Nagasaki University |
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Principal Investigator |
EGUCHI Katsumi Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (30128160)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAKAMI Atsushi Nagasaki University, Graduate School of Biomedical Sciences, Assistant, 大学院・医歯薬学総合研究科, 助手 (90325639)
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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 |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | apoptosis / NK cells / granzyme B / serine proteinase inhibitor / PI-9 / rheumatoid arthritis (RA) / macrophage-like synovial cells / IL-1β / PI-1β / 慢性関節リウマチ(RA) |
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| Research Abstract |
1) NK cell death and serpin proteinase inhibitor 9 (PI-9)
Here we show that NK cell activation is accompanied by the leakage of granzyme B from intracellular granules into the cytoplasm. Evidence for granzyme B leakage includes the formation of granzyme B/ serine proteinase inhibitor 9 (PI-9) complexes that are detected by immunoprecipitation as well as colocalization of granzyme B and PI-9 detected by immunocytochemistry. The proapoptotic molecule Bid, a specific substrate for granzyme B, was cleaved within 2 min following CD2-induced NK cell activation, suggesting that granzyme B triggers apoptosis by directing Bid to mitochondrial membranes. The granzyme B/PI-9 protein ratio was found to mirror the percentage of CD2-induced NK cell death, suggesting that an excess of leaked granzyme B over its inhibitor is a major determinant of cell death. We suggest that granzyme B leakage-induced cell death (GLCD) is an important determinant of activation-induced NK cell death and that this process may be important for the fate of NK cells which encounter malignant cells or virus-infected cells.
2) Rheumatoid arthritis (RA) and PI-9
We examined the titer of IL-1β and IL-18 in sera and synovium derived from same RA patients by ELISA. Both IL-1β and IL-18 were produced from RA synovium. In immunohistochemistry, PI-9 was stained in macrophage-like synovial cells (type A). Both caspase 1 and PI-9 were detected in RA synovium using western blotting study. The caspase 1/PI-9 protein ratio was found to mirror the production of IL-1β, but not IL-18 from synovium, suggesting that PI-9 may regulate IL-1β production via caspase 1 inhibition.
PI-9 plays the critical roles for the regulation of NK cell death and IL-1β production from RA synovium.
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