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Role of PI3-kinase in the development of mast cells and anti-helminth immunity

PI3激酶在肥大细胞发育和抗蠕虫免疫中的作用

基本信息

批准号：
14370116
负责人：
KOYASU Shigeo
金额：
$ 8.9万
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：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370116/
关键词：
p85α knockout mouse c-kit Strongyloides venezuelensis Th1 Th2 JNK

项目摘要

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 … More 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

我们利用p85α缺陷小鼠检测了IA类PI3K在肥大细胞分化中的作用，发现p85α缺陷小鼠选择性地缺乏胃肠道和腹膜肥大细胞，而在正常生理条件下，肥大细胞很容易在其他组织中找到，如皮肤。在p85α缺陷小鼠中持续观察到强烈的被动全身过敏反应，表明这些小鼠中的肥大细胞具有功能活性。缺乏c-Kit-PI3K信号通路可能是导致p85α缺陷小鼠肥大细胞独特发育障碍的机制，因为在p85α缺陷的肥大细胞中，干细胞因子诱导的增殖和JNK活性严重受损。由于干细胞因子诱导的肥大细胞的增殖需要jnk活性通过rac1的激活，因此jnk活性的受损可能导致p85α缺陷的肥大细胞对干细胞因子的反应中有丝分裂能力的缺陷。IA类PI3K对t-…中肥大细胞的分化也是至关重要的病原性免疫期较多。P85α基因缺陷小鼠在感染松材线虫的过程中表现出肥大细胞增多的严重缺陷。P85α基因缺陷小鼠肠系膜淋巴细胞产生IL-3的功能障碍可能是导致蠕虫感染过程中肥大细胞功能受损的主要原因。此外，在p85α缺陷小鼠中，肠系膜淋巴细胞对寄生虫抗原的反应产生Th2型细胞因子显著受损。除了IL-3的产生受损外，其他Th2型细胞因子的产生缺陷也可能影响肥大细胞增殖，导致p85α缺陷小鼠肠道线虫的延迟清除。事实上，过继转移经Th2细胞因子处理的骨髓来源的肥大细胞，而不是未经处理的肥大细胞，能够将驱除沙门氏菌的能力恢复到野生型水平。进一步证明，在p85α缺陷小鼠中，树突状细胞在微生物刺激下过度产生IL-12会导致Th1反应增强。我们的数据表明，IA类PI3K在调节Th1和Th2应答之间的平衡方面发挥着重要作用，特别是在诱导或抑制Th2或Th1应答方面。在p85α缺陷小鼠中，肥大细胞自主性(c-Kit介导的信号受损)和环境(Th1vsTh2的异常倾斜)缺陷可能导致肥大细胞增多症和随后对肠道线虫感染的免疫反应障碍。较少