期刊
INTERNATIONAL IMMUNOLOGY
卷 25, 期 4, 页码 215-220出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxs105
关键词
allergy; calcium mobilization; IgE; phosphorylation
类别
资金
- Japan Society for the Promotion of Science [14370116, 16390146, 18390155, 22590439]
- Takeda Science Foundation
- Keio University
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Grants-in-Aid for Scientific Research [16390146, 14370116, 22590439, 18390155, 23790546] Funding Source: KAKEN
Both Class IA and Class IB PI3Ks are required for optimal allergic responses.Class IA and IB phosphoinositide 3-kinases (PI3Ks) have been shown to regulate mast cell functions such as proliferation, development, survival and degranulation, but the functional redundancy between these two PI3K signaling pathways in mast cells remains unclear. Here, we have generated mice deficient in both class IA regulatory subunit p85 and class IB catalytic subunit p110, and show that p85(/)p110(/) mice exhibit a more severe defect in mast cell development than single-knockout mice. In addition, the in vivo passive cutaneous anaphylaxis reaction of p85(/)p110(/) mice was nearly completely abrogated, whereas single-knockout mice exhibit just marginal reduction. Pharmacological inactivation of Akt in wild-type bone marrow-derived mast cells (BMMCs) led to partial reduction of degranulation, while over-expression of a constitutively active Akt partially restored the impaired degranulation in p85(/)p110(/) BMMCs. We also found that the extracellular signal-regulated kinase (ERK) signaling pathway was activated in a PI3K-dependent manner upon FceRI stimulation and that simultaneous inhibition of Akt and ERK resulted in nearly complete blockade of FceRI-induced degranulation. Our data provide evidence that Akt and ERK pathways play redundant roles in FceRI-induced degranulation.
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