Essential role for the p110delta phosphoinositide 3-kinase in the allergic response

Nature. 2004 Oct 21;431(7011):1007-11. doi: 10.1038/nature02991.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphylaxis / enzymology
  • Anaphylaxis / immunology
  • Animals
  • Cell Adhesion / drug effects
  • Cell Count
  • Cell Degranulation / drug effects
  • Cell Movement / drug effects
  • Cytokines / metabolism
  • Dermis / cytology
  • Genes, Essential / genetics
  • Humans
  • Hypersensitivity / enzymology*
  • Hypersensitivity / immunology
  • Interleukin-3 / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mast Cells / cytology
  • Mast Cells / enzymology*
  • Mast Cells / immunology
  • Mast Cells / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, IgE / immunology
  • Second Messenger Systems / physiology
  • Stem Cell Factor / pharmacology

Substances

  • Cytokines
  • Interleukin-3
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, IgE
  • Stem Cell Factor
  • Pik3cd protein, mouse