Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110δ but Not p110γ Promotes Optimal Allergic Responses In Vivo

Abstract

The leukocyte-enriched p110γ and p110δ isoforms of PI3K have been shown to control in vitro degranulation of mast cells induced by cross-linking of the high affinity receptor of IgE (FcεRI). However, the relative contribution of these PI3K isoforms in IgE-dependent allergic responses in vivo is controversial. A side-by-side comparative analysis of the role of p110γ and p110δ in mast cell function, using genetic approaches and newly developed isoform-selective pharmacologic inhibitors, confirms that both PI3K isoforms play an important role in FcεRI-activated mast cell degranulation in vitro. In vivo, however, only p110δ was found to be required for optimal IgE/Ag-dependent hypersensitivity responses in mice. These observations identify p110δ as a key therapeutic target among PI3K isoforms for allergy- and mast cell-related diseases.