Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production.
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.
Zhang
Ting-Ting
TT
CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Okkenhaug
Klaus
K
Laboratory of Lymphocyte Signalling and Development, the Babraham Institute, Cambridge, United Kingdom.
Nashed
Baher F
BF
CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Puri
Kamal D
KD
Calistoga Pharmaceuticals, Seattle, Wash.
Knight
Zachary A
ZA
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, Calif.
Shokat
Kevan M
KM
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, Calif.
Vanhaesebroeck
Bart
B
Institute of Cancer, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom.
Marshall
Aaron J
AJ
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.
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
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