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

Shigeru Iwata, Kunihiro Yamaoka, Hiroaki Niiro, Kazuhisa Nakano, Sheau Pey Wang, Koichi Akashi, Yoshiya Tanaka

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 κB 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 κB, 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.

Original languageEnglish
Pages (from-to)1594-1601
Number of pages8
JournalJournal of Allergy and Clinical Immunology
Volume129
Issue number6
DOIs
Publication statusPublished - 2012 Jun
Externally publishedYes

Fingerprint

Toll-Like Receptors
B-Lymphocytes
TNF Receptor-Associated Factor 6
B-Lymphocyte Subsets
human SYK protein
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Toll-Like Receptor 9
CD40 Ligand
Autoimmune Diseases

Keywords

  • B cells
  • Syk
  • TNF receptor-associated factor 6
  • Toll-like receptor 9

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation. / Iwata, Shigeru; Yamaoka, Kunihiro; Niiro, Hiroaki; Nakano, Kazuhisa; Wang, Sheau Pey; Akashi, Koichi; Tanaka, Yoshiya.

In: Journal of Allergy and Clinical Immunology, Vol. 129, No. 6, 06.2012, p. 1594-1601.

Research output: Contribution to journalArticle

Iwata, Shigeru ; Yamaoka, Kunihiro ; Niiro, Hiroaki ; Nakano, Kazuhisa ; Wang, Sheau Pey ; Akashi, Koichi ; Tanaka, Yoshiya. / Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation. In: Journal of Allergy and Clinical Immunology. 2012 ; Vol. 129, No. 6. pp. 1594-1601.
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AB - 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 κB 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 κB, 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.

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