Role of phosphoinositide 3-kinase p110δ in TLR4-and TLR9-mediated B cell cytokine production and differentiation

被引:52
作者
Dil, Nyla [1 ,2 ,3 ]
Marshall, Aaron J. [2 ,3 ,4 ]
机构
[1] Univ Manitoba, Dept Oral Biol, Winnipeg, MB R3E 0W2, Canada
[2] Univ Manitoba, CIHR Natl Training Program Allergy & Asthma Res, Winnipeg, MB R3E 0W2, Canada
[3] Univ Manitoba, Dept Immunol, Winnipeg, MB R3E 0W2, Canada
[4] Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB R3E 0W2, Canada
基金
加拿大健康研究院;
关键词
B lymphocyte; Phosphoinositide; 3-kinase; Toll-like receptor; TLR4; TLR9; LPS; CpG; Cytokines; Immunoglobulins; Plasma cells; TOLL-LIKE RECEPTORS; CLASS-SWITCH RECOMBINATION; PHOSPHATIDYLINOSITOL; 3-KINASE; DENDRITIC CELLS; CPG DNA; T-BET; NEGATIVE REGULATION; IMMUNE-RESPONSES; IL-12; PRODUCTION; BACTERIAL-DNA;
D O I
10.1016/j.molimm.2009.03.010
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1970 / 1978
页数:9
相关论文
共 52 条
[1]   Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4 [J].
Aksoy, E ;
Vanden Berghe, W ;
Detienne, S ;
Amraoui, Z ;
Fitzgerald, KA ;
Haegeman, G ;
Goldman, M ;
Willems, F .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2005, 35 (07) :2200-2209
[2]   TLR-mediated stimulation of APC: Distinct cytokine responses of B cells and dendritic cells [J].
Barr, Tom A. ;
Brown, Sheila ;
Ryan, Gemma ;
Zhao, Jiexin ;
Gray, David .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2007, 37 (11) :3040-3053
[3]   A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells [J].
Bernasconi, NL ;
Onai, N ;
Lanzavecchia, A .
BLOOD, 2003, 101 (11) :4500-4504
[4]   A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation [J].
Clayton, E ;
Bardi, G ;
Bell, SE ;
Chantry, D ;
Downes, CP ;
Gray, A ;
Humphries, LA ;
Rawlings, D ;
Reynolds, H ;
Vigorito, E ;
Turner, M .
JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 196 (06) :753-763
[5]   MECHANISM OF THYMUS-INDEPENDENT IMMUNOCYTE TRIGGERING-MITOGENIC ACTIVATION OF B-CELLS RESULTS IN SPECIFIC IMMUNE-RESPONSES [J].
COUTINHO, A ;
GRONOWICZ, E ;
BULLOCK, WW ;
MOLLER, G .
JOURNAL OF EXPERIMENTAL MEDICINE, 1974, 139 (01) :74-92
[6]  
Díaz-Guerra MJM, 1999, J IMMUNOL, V162, P6184
[7]   Induction of in vitro reprogramming by toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages:: Effects of TLR "homotolerance" versus "heterotolerance" on NF-κB signaling pathway components [J].
Dobrovolskaia, MA ;
Medvedev, AE ;
Thomas, KE ;
Cuesta, N ;
Toshchakov, V ;
Ren, TB ;
Cody, MJ ;
Michalek, SM ;
Rice, NR ;
Vogel, SN .
JOURNAL OF IMMUNOLOGY, 2003, 170 (01) :508-519
[8]   TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE [J].
Ehlers, M ;
Fukuyama, H ;
McGaha, TL ;
Aderem, A ;
Ravetch, JV .
JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (03) :553-561
[9]   Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase [J].
Frasca, D ;
Van der Put, E ;
Riley, RL ;
Blomberg, BB .
JOURNAL OF IMMUNOLOGY, 2004, 172 (04) :2155-2162
[10]   Phosphoinositide kinases [J].
Fruman, DA ;
Meyers, RE ;
Cantley, LC .
ANNUAL REVIEW OF BIOCHEMISTRY, 1998, 67 :481-507