PI3K is a negative regulator of IgE production.
The production of IgE, a main player in allergic disorders such as asthma and atopic dermatitis, is strictly regulated and the serum concentrations of IgE are normally kept at a much lower level than other isotypes. We found that mice deficient for the p85alpha regulatory subunit of class IA phosphoinositide 3-kinase (PI3K) produced increasing amounts of serum IgE. Purified p85alpha-/- B cells produced more IgE than wild-type B cells in vitro in response to anti-CD40 mAb and IL-4. PI3K inhibitors wortmannin and IC87114 enhanced IgE production by wild-type B cells stimulated with anti-CD40 mAb and IL-4. Under the same condition, antigen receptor cross-linking induced the expression of inhibitor of differentiation-2 and suppressed the expression of activation-induced cytidine deaminase and class switch recombination (CSR) in a PI3K-dependent manner. IgE production was also suppressed in a concentrated cell culture condition, which was completely reversed by PI3K inhibition. The selective suppression of IgE production by PI3K was also observed at a protein level after CSR. Our results indicate that PI3K negatively regulates IgE production at both CSR and protein levels.
Doi
Tomomitsu
T
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Obayashi
Kunie
K
Kadowaki
Takashi
T
Fujii
Hideki
H
Koyasu
Shigeo
S
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000937:Antigen-Antibody Reactions; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation; D020869:Gene Expression Profiling; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000906:Antibodies; D003564:Cytidine Deaminase; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors