+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



Journal of Allergy and Clinical Immunology 129(6): 1594-601.E2



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. 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. 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. 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. 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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 051459642

Download citation: RISBibTeXText

PMID: 22541243

DOI: 10.1016/j.jaci.2012.03.014


Related references

Involvement of protein tyrosine kinase in Toll-like receptor 4-mediated NF-kB activation in human peripheral blood monocytes. American Journal of Physiology 284(4): 07-L613, 2003

Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling. Proceedings of the National Academy of Sciences of the United States of America 89(3): 1118-1122, 1992

Involvement of protein tyrosine kinase in Toll-like receptor 4-mediated NF-kappa B activation in human peripheral blood monocytes. American Journal of Physiology. Lung Cellular and Molecular Physiology 284(4): L607-L613, 2003

T cell receptor signaling mediated by the Fyn tyrosine kinase leads to partial activation. FASEB Journal 12(5): A939, 1998

Toll-like receptor 4 mediates retinal ischemia/reperfusion injury through nuclear factor-κB and spleen tyrosine kinase activation. Investigative Ophthalmology and Visual Science 54(8): 5807-5816, 2013

Poly -induced Toll-like receptor 3 -mediated activation of NFkappaB and MAP kinase is through an interleukin-1 receptor-associated kinase -independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR. Journal of Biological Chemistry 278(19): 16713-16719, 2003

Bruton's tyrosine kinase is dispensable for the Toll-like receptor-mediated activation of mast cells. Cellular Signalling 21(1): 79-86, 2009

Overexpression of human stem cell factor impairs melanocyte, mast cell, and thymocyte development: a role for receptor tyrosine kinase-mediated mitogen activated protein kinase activation in cell differentiation. Blood 90(8): 3018-3026, 1997

Tyrosine kinase Syk associates with toll-like receptor 4 and regulates signaling in human monocytic cells. Immunology and Cell Biology 85(3): 249-256, 2007

Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR. Journal of Biological Chemistry 278(19): 16713-9, 2003

Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circulation Research 104(2): 210-8 21p Following 218, 2009

Poly(dIcntdotdC)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappaB and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR. Journal of Biological Chemistry 278(19): 16713-16719, 2003

Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor kB Activation by Toll-like Receptor 4. The Journal of Biological Chemistry 278(28): 258-64, 2003

Expression of the Receptor Tyrosine Kinase EphB2 on Dendritic Cells Is Modulated by Toll-Like Receptor Ligation but Is Not Required for T Cell Activation. Plos one 10(9): E0138835, 2015

T-Cell receptor signaling pathway exerts a negative control on thrombin-mediated increase in [Ca2+]i and p38 MAPK activation in Jurkat T cells: implication of the tyrosine kinase p56Lck. Blood 91(11): 4232-4241, 1998