Role of PI3-kinase in the development of mast cells and anti-helminth immunity
| Project/Area Number |
14370116
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | KEIO UNIVERSITY |
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Principal Investigator |
KOYASU Shigeo Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | p85α / knockout mouse / c-kit / Strongyloides venezuelensis / Th1 / Th2 / JNK |
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| Research Abstract |
We examined the role of class IA PI3K in mast cell differentiation using p85α-deficient mice and found that p85α-deficient mice selectively lack gastrointestinal and peritoneal mast cells whereas mast cells are readily found in other tissues such as skin under normal physiological conditions. Strong passive systemic anaphylaxis was consistently observed in p85α-deficient mice, suggesting that mast cells in these mice are functionally competent. The lack of the c-Kit-PI3K signaling pathway seems the mechanism accounting for the unique developmental impairment of mast cells in p85α-deficient mice as proliferation and JNK activation in response to SCF was severely impaired in p85α-deficient mast cells. Since SCF-induced proliferation of mast cells requires JNK activity through Rac1 activation, impairment in JNK activation may cause the defective mitogenic capacity of p85α-deficient mast cells in response to SCF. The class IA PI3K is also critical for the differentiation of mast cells in t
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he pathogenic immune phase. The p85α-deficient mice demonstrated severe defects in mastocytosis during infection by Strongyloides venezuelensis. Impaired IL-3 production by mesenteric lymphocytes in p85α-deficient mice is likely the main defect leading to impaired mastocytosis during helminth infection. Furthermore, production of Th2 cytokines by mesenteric lymphocytes in response to the parasites' antigens was dramatically impaired in p85α-deficient mice. In addition to the impaired IL-3 production, defective production of other Th2 cytokines may influence mastocytosis, resulting in the delayed clearance of intestinal nematodes in p85α-deficient mice. Indeed, adoptive transfer of bone marrow-derived mast cells pretreated with Th2 cytokines but not untreated mast cells was able to restore the ability to expel S. venezuelensis to wild type levels. It was further demonstrated that hyperproduction of IL-12 by dendritic cells in response to microbial stimuli in p85α-deficient mice causes an enhanced Th1 response. Our data show that class IA PI3K plays an important role in the regulation of the balance between Th1 and Th2 responses, especially in the induction or suppression of Th2 or Th1 responses, respectively. In p85α-deficient mice, both mast cell autonomous (impaired c-Kit-mediated signal) and environmental (abnormal skewing of Th1 vs Th2) defects likely contribute to the defective mastocytosis and subsequent impairment in immune response against intestinal nematode infection. Less
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Report
(3 results)
Research Products
(13 results)
