The p110 isoform of PI(3)K is a key regulator of mast cell homeostasis and the allergic response.
Mast cells release inflammatory substances to trigger and maintain the allergic response. Their differentiation and activation are regulated by the stem-cell factor (SCF) and immunoglobulin E (IgE) signaling pathways, respectively. Activation of SCF receptors and engagement of IgE by allergen result in downstream phosphatidylinositol-3-OH kinase (PI(3)K) signaling. Ali et al. now report that specific inactivation of the PI(3)K p110 isoform protects mice against anaphylactic allergic responses.
Leukocytes primarily express the p110 catalytic subunit isoform of PI(3)K, as opposed to the ubiquitously expressed p110 and p110 isoforms. To investigate the role of p110 in leukocytes, the authors isolated bone-marrow mast cells (BMMCs) from mice harboring a p110 loss-of-function mutation (p110D910A/D910A). p110-mutant BMMCs exhibited defects in proliferation and had reduced levels of interleukin-3 (IL-3; a mast cell proliferation and differentiation factor) and/or SCF-induced DNA synthesis. Moreover, their ability to adhere to fibronectin or migrate towards SCF was severely impaired when compared with wild-type cells.
By using a series of in vitro studies, the authors showed that, in p110-mutant BMMCs, SCF- or IL-3 -induced phosphorylation of PKB was severely reduced, or even absent, whereas phosphorylation of Erk remained unaffected. In addition, they demonstrated that total class IA PI(3)K activity was reduced by up to 90%. Thus, they concluded that the p110 isoform was a major contributor to PI(3)K signaling downstream of both SCF and IL-3.
To strengthen the physiological significance of their findings, Ali et al. examined the capacity of mutant BMMCs to release inflammatory mediators in response to antigen in complex with IgE. They showed that p110D910A/D910A BMMCs exhibited a 50% reduction in FcRI-induced degranulation, compared with wild-type cells. Consistently, pre-incubation of wild-type BMMCs or human mast cells with a specific p110 inhibitor reduced degranulation to similar levels and also blocked the capacity of SCF to potentiate degranulation by low doses of antigen, while leaving mutant BMMCs unaffected. p110D910A/D910A BMMCs were also defective in the release of inflammatory cytokines such as interleukin-6 (IL-6) and tumor-necrosis factor (TNF – ).
Finally, the authors examined the ability of p110D910A/D910A mice to respond to immune challenge in a passive cutaneous anaphylaxis (PCA) model. They observed that PCA was markedly reduced in both the ear and back dermis of mutant mice, and that this result could be mimicked by treating mice with a p110-specific inhibitor. Collectively, the work by Ali et al. demonstrates an important role for the p110 isoform of PI(3)K in immune homeostasis and mast-cell allergies, and has wider implications in designing specific PI(3)K compounds for therapeutic intervention.
Myrto Raftopoulou Signaling Gateway
References
Ali, Khaled, Bilancio, , Thomas, Matthew, Pearce, Wayne, Gilfillan, Alasdair M, Tkaczyk, Christine, Kuehn, Nicolas, Gray, Alexander, Giddings, June, Peskett, Emma, Fox, Roy, Bruce, Ian, Walker, Christoph, Sawyer, Carol, Okkenhaug, Klaus, Finan, Peter, & Vanhaesebroeck, Bart Essential role for the p110d phosphoinositide 3-kinase in the allergic response. Nature431, 1007–1011 (21 October 2004); 10.1038/nature02991 | Article | PubMed |
isoform of PI(3)K is a key regulator of mast cell homeostasis and the allergic response.
and p110
isoforms. To investigate the role of p110
RI-induced degranulation, compared with wild-type cells. Consistently, pre-incubation of wild-type BMMCs or human mast cells with a specific p110