| Project/Area Number |
15591046
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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 |
膠原病・アレルギー・感染症内科学
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| Research Institution | Chiba University |
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Principal Investigator |
NAKAJIMA Hiroshi Chiba University Hospital, Assistant Professor, 医学部附属病院, 助手 (00322024)
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| Co-Investigator(Kenkyū-buntansha) |
IWAMOTO Itsuo Chiba University, Graduate School of Medicine, Associate Professor, 大学院・医学研究院, 助教授 (10111436)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Stat6 / Stat5 / protease / ONO-5046 / elastase / mast cells / 気管支喘息 / エラスターゼ / 核内蛋白 |
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| Research Abstract |
Accumulating evidence suggests that STAT-mediated signaling plays critical roles in cell differentiation and/or cell expansion and that thus, STAT-mediated signaling is regulated strictly by many mechanisms. In murine mast cells, when Stat6 is activated by IL-4 and translocated to the nucleus, Stat6 is cleaved by a nucleus-associated protease (namely Stat6-protease). Similarly, the activated Stat5 is cleaved by a protease (Stat5-protease) in the nucleus of myeloid progenitors. These STAT proteases cleave the corresponding STAT proteins at the carboxyl-terminus and the resultant STAT proteins function as dominant negative molecules. Functionally, Stat6-protease protects mast cells from Stat6-dependent growth inhibition while Stat5-protease maintains the immature state of myeloid progenitors. These findings indicate that the proteolytic processing of STAT proteins by the nucleus-associated protease functions as a lineage-specific negative-regulator of STAT-mediated signaling.
In the present study, we further characterized these Stat proteases. Interestingly, the activity of Stat6 protease but not of Stat5 protease was inhibited by ONO-5046, a narrow-spectrum elastase inhibitor that inhibits the activity of neutrophil elastase(NE) and proteinase 3(PR3) but not of cathepsin G. Although both NE and PR3 were expressed in bone marrow-derived mast cells and were capable to cleave Stat6 in vitro, our results demonstrated that NE and PR3 differed from mast cell-specific Stat6 protease. These results suggest that Stat6 protease may be an NE-like protease that is exclusively expressed in the nucleus of mast cells.
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