Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation
Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation
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DOI：
10.1016/j.jaci.2012.03.014
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发表时间：
2012-06-01
影响因子：
14.2
通讯作者：
Tanaka, Yoshiya
中科院分区：
文献类型：
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作者：
Iwata, Shigeru;Yamaoka, Kunihiro;Tanaka, Yoshiya
背景：B 细胞由 B 细胞受体 (BCR) 和 CD40 的组合信号激活。然而，BCR 信号与人 B 细胞中 Toll 样受体 (TLR) 信号协同作用的潜在机制仍不清楚。 目的：我们试图阐明脾酪氨酸激酶 (Syk)（BCR 信号传导的关键分子）在 TLR 介导的人 B 细胞激活中的作用。方法：用抗 BCR、可溶性 CD40 配体和 CpG 的组合刺激人幼稚和记忆 B 细胞。评估了 Syk 抑制剂对多种 B 细胞功能以及 B 细胞中 TLR9、TNF 受体相关因子 (TRAF) 和磷酸核因子 kappa B 表达的影响。结果：BCR 的激活与 CD40 和 TLR9 介导的信号协同作用，驱动人类 B 细胞亚群（尤其是记忆 B 细胞）的强劲增殖、细胞周期进展、共刺激分子的表达、细胞因子产生和免疫球蛋白产生。然而，Syk 抑制剂显着消除了这些 B 细胞功能。值得注意的是，在通过所有 3 个受体刺激后，B 细胞亚群诱导了 TLR9、TRAF6 和磷酸核因子 kB 的显着表达，而 Syk 抑制剂再次显着消除了这种表达。 结论：Syk 介导的 BCR 信号传导是最佳诱导 TLR9 和 TRAF6 的先决条件，从而允许 TLR9 介导的信号传导在记忆 B 细胞中有效传播。这些结果还强调了 Syk 在自身免疫性疾病患者异常 B 细胞激活中的作用。 （过敏临床免疫杂志 2012 年；129：1594-601。）
Background: B cells are activated by combined signals through the B-cell receptor (BCR) and CD40. However, the underlying mechanisms by which BCR signals synergize with Toll-like receptor (TLR) signaling in human B cells remain unclear.Objective: We sought to elucidate a role of spleen tyrosine kinase (Syk), a key molecule of BCR signaling, in TLR-mediated activation of human B cells.Methods: Human naive and memory B cells were stimulated with combinations of anti-BCR, soluble CD40 ligand, and CpG. Effects of the Syk inhibitors on several B-cell functions and expression of TLR9, TNF receptor-associated factors (TRAFs), and phospho-nuclear factor kappa B in B cells were assessed.Results: Activation of BCR synergized with CD40- and TLR9-mediated signals in driving robust proliferation, cell-cycle progression, expression of costimulatory molecules, cytokine production, and immunoglobulin production of human B-cell subsets, especially memory B cells. However, the Syk inhibitors remarkably abrogated these B-cell functions. Notably, after stimulation through all 3 receptors, B-cell subsets induced marked expression of TLR9, TRAF6, and phospho-nuclear factor kB, which was again significantly abrogated by the Syk inhibitors.Conclusion: Syk-mediated BCR signaling is a prerequisite for optimal induction of TLR9 and TRAF6, allowing efficient propagation of TLR9-mediated signaling in memory B cells. These results also underscore the role of Syk in aberrant B-cell activation in patients with autoimmune diseases. (J Allergy Clin Immunol 2012; 129: 1594-601.)