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Role of PI3-kinase in the development and function of mast cells

PI3激酶在肥大细胞发育和功能中的作用

基本信息

批准号：
16390146
负责人：
KOYASU Shigeo
金额：
$ 9.54万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390146/
关键词：
p85α knockout mouse SCF c-kit integrin IL-3 ケモカイン接着分子

项目摘要

Role of class I_A PI3K in mast cell differentiation was examined using p85α-deficient mice. We have 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. We studied why p85α-deficient mice lack only gastrointestinal mast cells. We first examined the mast cell precursor frequency in the bone marrow, spleen and intestinal tract, by limiting dilution method. It was revealed that the precursor frequency in the intestine was less than 10% of wild type level whereas those of the bone marrow and spleen were unaffected compared to wild type mice. These results suggest that either the survival of progenitors and/or mature mast cell in the intestine or the migration of precursor cells to the intestine is impaired in p85α-deficient mice. We found that c-Kit signal is strongly impaired in p85α-deficient mast cells established from the bone marrow with IL-3 as proliferation and JNK activation in response to SCF was severely impaired in p85α-deficient cultured mast cells. We also examined the expression and function of integrins that are known to be important in cell migration. We found that expression of α4β7 integrin that is critical for cellular migration to the intestine was normal in p85α-deficient mast cells but the binding of α4β7 to its ligand, MAdCAM was significantly weaker than that of wild type mast cells. We conclude from these observations that the lack of gastrointestinal mast cells in p85α-deficient mice is due to the deficiency in both migration to and survival in the intestine.

用p85α缺陷小鼠研究I_A类PI 3 K在肥大细胞分化中的作用。我们发现p85α缺陷小鼠选择性缺乏胃肠道和腹膜肥大细胞，而肥大细胞在正常生理条件下很容易在其他组织如皮肤中发现。我们研究了为什么p85α缺陷小鼠只缺乏胃肠道肥大细胞。我们首先用有限稀释法检测了骨髓、脾脏和肠道中肥大细胞前体的频率。结果表明，与野生型小鼠相比，肠中的前体频率低于野生型水平的10%，而骨髓和脾脏中的前体频率未受影响。这些结果表明，在p85α缺陷小鼠中，前体细胞和/或成熟肥大细胞在肠道中的存活或前体细胞向肠道的迁移受到损害。我们发现，在p85 α缺陷的肥大细胞中，c-Kit信号被强烈地削弱，而在p85α缺陷的肥大细胞中，IL-3作为增殖的应答SCF的JNK活化被严重地削弱。我们还研究了已知在细胞迁移中重要的整合素的表达和功能。我们发现，在p85α缺陷型肥大细胞中，α4β7整合素的表达是正常的，但α4β7与其配体MAdCAM的结合明显弱于野生型肥大细胞。我们从这些观察结果中得出结论，p85α缺陷小鼠中胃肠道肥大细胞的缺乏是由于向肠道的迁移和在肠道中的存活不足。