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Cellular and Molecular Life Sciences

, Volume 72, Issue 11, pp 2223–2236 | Cite as

Syk is indispensable for CpG-induced activation and differentiation of human B cells

  • Mariann Kremlitzka
  • Bernadett Mácsik-Valent
  • Anna ErdeiEmail author
Research Article

Abstract

B cells are efficiently activated by CpG oligodeoxynucleotides (ODNs) to produce pro-inflammatory cytokines and antibody (Ab). Here, we describe a so far unidentified, spleen tyrosine kinase (Syk)-dependent pathway, which is indispensable for CpG-induced human B cell activation. We show that triggering of B cells by CpG results in Syk and src kinase phosphorylation, proliferation, as well as cytokine and Ab production independent of the BCR. Notably, all these functions are abrogated when Syk is inhibited. We demonstrate that CpG-induced Syk activation originates from the cell surface in a TLR9-dependent manner. While inhibition of Syk does not influence the uptake of CpG ODNs, activation of the kinase is a prerequisite for the delivery of CpG into TLR9-containing endolysosomes and for the CpG-induced up-regulation of TLR9 expression. Our results reveal an alternative, Syk-dependent pathway of CpG-induced B cell stimulation, which is initiated at the plasma membrane and seems to be an upstream requirement for endosomal TLR9-driven B cell proliferation and differentiation.

Keywords

B cells TLR9 Syk Cell activation Signal transduction 

Abbreviations

ODN

Oligodeoxynucleotide

TLR

Toll-like receptor

MyD88

Myeloid differentiating factor 88

Syk

Spleen tyrosine kinase

BCR

B cell receptor

MAPK

Mitogen-activated protein kinase

LAMP-1

Lysosome-associated membrane protein-1

Notes

Acknowledgments

We thank Gabriella Sármay for critical reading of the manuscript and János Matkó for his valuable assistance in confocal microscopy. This work has been financially supported by TÁMOP 4.2.1./B-09/1/KMR-2010-0003, the Hungarian Academy of Sciences and the Hungarian Scientific Research Fund—OTKA 112011.

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Mariann Kremlitzka
    • 2
  • Bernadett Mácsik-Valent
    • 1
  • Anna Erdei
    • 1
    • 2
    Email author
  1. 1.Department of ImmunologyEötvös Loránd UniversityBudapestHungary
  2. 2.MTA-ELTE Immunology Research GroupBudapestHungary

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