Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation

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• 作者：Shigeru Iwata ; MD ; PhD^a ; Kunihiro Yamaoka ; MD ; PhD^a ; Hiroaki Niiro ; MD ; PhD^b ; Kazuhisa Nakano ; MD ; PhD^a ; Sheau-Pey Wang ; MS^a ; Koichi Akashi ; MD ; PhD^b ; Yoshiya Tanaka ; MD ; PhD^a ; ^{tanaka@med.uoeh-u.ac.jp}
• 关键词：Syk ; Toll-like receptor 9 ; TNF receptor&ndash ; associated factor 6 ; B cells
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 期刊代码：158_00916749
• 类别：med
• 出版时间：June, 2012
• 卷：129
• 期：6
• 页码：1594-1601.e2
• 文件大小：1395 K

摘要

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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 魏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聽expression of TLR9, TRAF6, and phospho-nuclear factor聽魏B, 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.