title: Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iwata
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Sheau-Pey
authors.initials: SP
authors.lastname: Wang
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007156:Immunologic Memory; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D048029:TNF Receptor-Associated Factor 6; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase