Essential role for the p110delta phosphoinositide 3-kinase in the allergic response.
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.
Ali
Khaled
K
Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK.
Bilancio
Antonio
A
Thomas
Matthew
M
Pearce
Wayne
W
Gilfillan
Alasdair M
AM
Tkaczyk
Christine
C
Kuehn
Nicolas
N
Gray
Alexander
A
Giddings
June
J
Peskett
Emma
E
Fox
Roy
R
Bruce
Ian
I
Walker
Christoph
C
Sawyer
Carol
C
Okkenhaug
Klaus
K
Finan
Peter
P
Vanhaesebroeck
Bart
B
D000707:Anaphylaxis / Q000201:enzymology / Q000276:immunology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000378:metabolism; D020405:Dermis / Q000166:cytology; D020043:Genes, Essential / Q000235:genetics; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology* / Q000276:immunology; D007377:Interleukin-3 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017455:Receptors, IgE / Q000276:immunology; D015290:Second Messenger Systems / Q000502:physiology; D019089:Stem Cell Factor / Q000494:pharmacology
D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D007377:Interleukin-3; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017455:Receptors, IgE; D019089:Stem Cell Factor; C421683:Pik3cd protein, mouse