Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 129, Issue 6, Pages 1594-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.03.014
Keywords
Syk; Toll-like receptor 9; TNF receptor-associated factor 6; B cells
Categories
Funding
- Ministry of Health, Labor and Welfare of Japan
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- University of Occupational and Environmental Health, Japan
- Grants-in-Aid for Scientific Research [24591450] Funding Source: KAKEN
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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 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.)
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