Role of phosphoinositide 3-kinase p110 delta in TLR4- and TLR9-mediated B cell cytokine production and differentiation.
Phosphoinositide 3-kinase (PI3K) enzymes play key roles in signaling via antigen receptors and cytokine receptors and isoform-selective PI3K inhibitors are being evaluated as targets for treatment of allergic and inflammatory diseases. The specific roles of PI3K isoforms in TLR-mediated activation of lymphocytes have not been defined. In this study we assess the role of p110 delta PI3K in TLR4, TLR9, or TLR4+TLR9-mediated B cell responses. Utilizing both p110 delta-mutant mice and p110 delta-specific inhibitor IC87114, we find that signaling via p110 delta is required for optimal B cell proliferation, but is not required for TLR-mediated B cell differentiation into plasma cells or Ig isotype switch. However PI3K blockade led to increased frequencies of IgG1 and IgE expressing cells, and partially reversed ability of CpG to inhibit IgG1 and IgE. Examination of B cell cytokine production revealed that p110 delta blockade markedly reduced IL-6 and IL-10 production. In contrast, p110 delta signaling was clearly not required for IL-12 production, with p110 delta-mutant B cells in fact showing enhanced IL-12 p70 production. TLR4- and TLR9-ligands act in synergy to drive IL-6 and IL-10 production, but not IL-12, and this additive effect is independent of p110 delta signaling. Together, these results indicate that PI3K delta functions in influencing the type of B cell cytokine production and differentiation response induced by TLR-ligands.
Department of Immunology, University of Manitoba, Winnipeg, MB, R3E 0W2, Canada. dil@cc.umanitoba.ca
Nyla
N
Dil
Aaron J
AJ
Marshall
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis*; D017578:Immunoglobulin Class Switching / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010950:Plasma Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*
D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C408982:CPG-oligonucleotide; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse