TGFβ activated kinase 1 (TAK1) at the crossroad of B cell receptor and toll-like receptor 9 signaling pathways in human B cells

Dániel Szili, Zsuzsanna Bankó, Eszter Angéla Tóth, György Nagy, Bernadette Rojkovich, Tamás Gáti, Melinda Simon, Zoltán Hérincs, G. Sármay

Research output: Contribution to journalArticle

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Abstract

B cell development and activation are regulated by combined signals mediated by the B cell receptor (BCR), receptors for the B-cell activating factor of the tumor necrosis factor family (BAFF-R) and the innate receptor, Toll-like receptor 9 (TLR9). However, the underlying mechanisms by which these signals cooperate in human B cells remain unclear. Our aim was to elucidate the key signaling molecules at the crossroads of BCR, BAFF-R and TLR9 mediated pathways and to follow the functional consequences of costimulation.Therefore we stimulated purified human B cells by combinations of anti-Ig, B-cell activating factor of the tumor necrosis factor family (BAFF) and the TLR9 agonist, CpG oligodeoxynucleotide. Phosphorylation status of various signaling molecules, B cell proliferation, cytokine secretion, plasma blast generation and the frequency of IgG producing cells were investigated. We have found that BCR induced signals cooperate with BAFF-R- and TLR9-mediated signals at different levels of cell activation. BCR and BAFF- as well as TLR9 and BAFF-mediated signals cooperate at NF kB activation, while BCR and TLR9 synergistically costimulate mitogen activated protein kinases (MAPKs), ERK, JNK and p38. We show here for the first time that the MAP3K7 (TGF beta activated kinase, TAK1) is responsible for the synergistic costimulation of B cells by BCR and TLR9, resulting in an enhanced cell proliferation, plasma blast generation, cytokine and antibody production. Specific inhibitor of TAK1 as well as knocking down TAK1 by siRNA abrogates the synergistic signals. We conclude that TAK1 is a key regulator of receptor crosstalk between BCR and TLR9, thus plays a critical role in B cell development and activation.

Original languageEnglish
Article numbere96381
JournalPLoS One
Volume9
Issue number5
DOIs
Publication statusPublished - May 6 2014

Fingerprint

Toll-Like Receptor 9
B-lymphocytes
phosphotransferases (kinases)
B-Lymphocytes
Phosphotransferases
Cells
receptors
B-Cell Activation Factor Receptor
Chemical activation
Cell proliferation
mitogen-activated protein kinase
Tumor Necrosis Factor-alpha
B-Cell Activating Factor
Interleukin-4 Receptors
Cytokines
Plasmas
tumor necrosis factors
Phosphorylation
Molecules
Toll-like receptor 9

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

TGFβ activated kinase 1 (TAK1) at the crossroad of B cell receptor and toll-like receptor 9 signaling pathways in human B cells. / Szili, Dániel; Bankó, Zsuzsanna; Tóth, Eszter Angéla; Nagy, György; Rojkovich, Bernadette; Gáti, Tamás; Simon, Melinda; Hérincs, Zoltán; Sármay, G.

In: PLoS One, Vol. 9, No. 5, e96381, 06.05.2014.

Research output: Contribution to journalArticle

Szili, Dániel ; Bankó, Zsuzsanna ; Tóth, Eszter Angéla ; Nagy, György ; Rojkovich, Bernadette ; Gáti, Tamás ; Simon, Melinda ; Hérincs, Zoltán ; Sármay, G. / TGFβ activated kinase 1 (TAK1) at the crossroad of B cell receptor and toll-like receptor 9 signaling pathways in human B cells. In: PLoS One. 2014 ; Vol. 9, No. 5.
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AU - Nagy, György

AU - Rojkovich, Bernadette

AU - Gáti, Tamás

AU - Simon, Melinda

AU - Hérincs, Zoltán

AU - Sármay, G.

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