Essential role for the p110delta phosphoinositide 3-kinase in the allergic response |
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Authors: | Ali Khaled Bilancio Antonio 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 |
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Affiliation: | Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK. |
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Abstract: | Inflammatory substances released by mast cells induce and maintain the allergic response. Mast cell differentiation and activation are regulated, respectively, by stem cell factor (SCF; also known as Kit ligand) and by allergen in complex with allergen-specific immunoglobulin E (IgE). Activated SCF receptors and high-affinity receptors for IgE (FcvarepsilonRI) engage phosphoinositide 3-kinases (PI(3)Ks) to generate intracellular lipid second messenger signals. Here, we report that genetic or pharmacological inactivation of the p110delta isoform of PI(3)K in mast cells leads to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Inactivation of p110delta protects mice against anaphylactic allergic responses. These results identify p110delta as a new target for therapeutic intervention in allergy and mast-cell-related pathologies. |
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