Role of phosphoinositide 3-kinase p110δ in TLR4-and TLR9-mediated B cell cytokine production and differentiation
Role of phosphoinositide 3-kinase p110δ in TLR4-and TLR9-mediated B cell cytokine production and differentiation
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DOI：
10.1016/j.molimm.2009.03.010
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发表时间：
2009-06-01
影响因子：
3.6
通讯作者：
Marshall, Aaron J.
中科院分区：
文献类型：
--
作者：
Dil, Nyla;Marshall, Aaron J.
磷脂酰肌醇3-激酶(PI3K)酶通过抗原受体和细胞因子受体在信号转导中起关键作用，异构体选择性PI3K抑制剂正被评估为治疗变态反应性和炎症性疾病的靶点。PI3K亚型在TLR介导的淋巴细胞活化中的具体作用尚未确定。在这项研究中，我们评估了p110βPI3K在TLR4、TLR9或TLR4+TLR9介导的B细胞反应中的作用。利用p110 Delta突变小鼠和p110 Delta特异性抑制剂IC87114，我们发现通过p110 Delta的信号是最佳B细胞增殖所必需的，但不是TLR介导的B细胞分化为浆细胞或Ig同型转换所必需的。但阻断PI3K后，表达IgG1和IgE的细胞比例增加，部分逆转了CpG抑制IgG1和IgE的能力。B细胞细胞因子产生检测显示，p110 Delta阻断可显著降低IL-6和IL-10的产生。相比之下，p110 Delta信号显然不是IL-12产生所必需的，p110 Delta突变的B细胞实际上显示出IL-12 p70的产生增强。TLR4-和TLR9-配体协同作用促进IL-6和IL-10的产生，而不是IL-12的产生，并且这种相加作用不依赖于p110 Delta信号。综上所述，这些结果表明，PI3K Delta在影响TLR配体诱导的B细胞细胞因子的产生和分化反应中发挥作用。(C)2009爱思唯尔有限公司。保留所有权利。
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.