Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo.
The leukocyte-enriched p110gamma and p110delta 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 (FcepsilonRI). 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 p110gamma and p110delta in mast cell function, using genetic approaches and newly developed isoform-selective pharmacologic inhibitors, confirms that both PI3K isoforms play an important role in FcepsilonRI-activated mast cell degranulation in vitro. In vivo, however, only p110delta was found to be required for optimal IgE/Ag-dependent hypersensitivity responses in mice. These observations identify p110delta as a key therapeutic target among PI3K isoforms for allergy- and mast cell-related diseases.
Ali
Khaled
K
Centre for Cell Signalling, Institute of Cancer, Queen Mary University of London, Sir John Vane Research Centre, Charterhouse Square, London, United Kingdom.
Camps
Montserrat
M
Pearce
Wayne P
WP
Ji
Hong
H
Rückle
Thomas
T
Kuehn
Nicolas
N
Pasquali
Christian
C
Chabert
Christian
C
Rommel
Christian
C
Vanhaesebroeck
Bart
B
D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects / Q000235:genetics; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D000939:Epitopes / Q000502:physiology; D006967:Hypersensitivity / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007073:Immunoglobulin E / Q000502:physiology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000502:physiology
D058534:Class I Phosphatidylinositol 3-Kinases; D000939:Epitopes; D007073:Immunoglobulin E; D018836:Inflammation Mediators; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017452:Receptors, IgG; C485701:Fcgr1 protein, mouse; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C421683:Pik3cd protein, mouse