title: Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production.
abstract: BACKGROUND
  Recent studies indicate that pharmaceutical blockade of phosphoinositide 3-kinase (PI3K) signaling enzymes might be effective in reducing allergic airway inflammation. Signals generated by the p110delta PI3K isoform play critical roles in signaling through antigen and cytokine receptors and were shown to be required for induction of type 2, but not type 1, cytokine responses.
  
  
  OBJECTIVE
  We sought to determine the effect of genetic or pharmaceutical inactivation of p110delta PI3K on induction of IgE responses.
  
  
  METHODS
  We determined the effect of p110delta inactivation on induction of systemic IgE responses and on the ability of purified B lymphocytes to undergo IgE isotype switch in vitro. IgG and IgE germline transcription, postswitch transcription, protein expression, and secretion were measured, as well as cell division and expression of activation-induced cytidine deaminase, an enzyme required for isotype switch.
  
  
  RESULTS
  Paradoxically, inactivation of p110delta PI3K led to markedly increased IgE responses, despite reduced production of other antibody isotypes. This result was seen by using genetic inactivation of p110delta inhibition with IC87114 compound or blockade with the broad-spectrum PI3K inhibitors PIK-90 and PI-103. Significant increases in IgG1/IgE double-positive cells were observed, indicating that inactivation of PI3K leads to uncontrolled sequential switching from IgG1 to IgE. Disruption of p110delta signaling results in increased germline transcription at the epsilon locus and increased activation-induced cytidine deaminase expression, suggesting deregulation at the level of the isotype switch process.
  
  
  CONCLUSIONS
  Blockade of PI3K signaling leads to markedly enhanced B-cell switch to IgE and increased IgE levels in vivo, despite reduced type 2 cytokine production.
authors.affiliation: CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, the Babraham Institute, Cambridge, United Kingdom.
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.affiliation: CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Baher F
authors.initials: BF
authors.lastname: Nashed
authors.affiliation: Calistoga Pharmaceuticals, Seattle, Wash.
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.affiliation: Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, Calif.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Knight
authors.affiliation: Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, Calif.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: Institute of Cancer, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: marshall@ms.umanitoba.ca.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Marshall
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D003564:Cytidine Deaminase; D004791:Enzyme Inhibitors; D005663:Furans; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C522973:PI103; C421683:Pik3cd protein, mouse