Class I PI3K-mediated Akt and ERK signals play a critical role in FcεRI-induced degranulation in mast cells

Abstract

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 p85a and class IB catalytic subunit p110γ, and show that p85a-/-p110γ-/- mice exhibit a more severe defect in mast cell development than singleknockout mice. In addition, the in vivo passive cutaneous anaphylaxis reaction of p85a-/-p110γ-/- 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 p85a-/-p110γ-/- 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 FcεRI-induced degranulation. © The Japanese Society for Immunology. 2012. All rights reserved.