PMID- 24801688 OWN - NLM STAT- MEDLINE DCOM- 20150112 LR - 20220303 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 5 DP - 2014 TI - TGFbeta activated kinase 1 (TAK1) at the crossroad of B cell receptor and Toll-like receptor 9 signaling pathways in human B cells. PG - e96381 LID - 10.1371/journal.pone.0096381 [doi] LID - e96381 AB - 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 NFkappaB 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. FAU - Szili, Daniel AU - Szili D AD - Department of Immunology, Eotvos Lorand University, Budapest, Hungary. FAU - Banko, Zsuzsanna AU - Banko Z AD - Department of Immunology, Eotvos Lorand University, Budapest, Hungary. FAU - Toth, Eszter Angela AU - Toth EA AD - Department of Immunology, Eotvos Lorand University, Budapest, Hungary. FAU - Nagy, Gyorgy AU - Nagy G AD - Buda Hospital of Hospitaller Brothers of St. John, Budapest, Hungary; Department of Rheumatology, Semmelweis University, Budapest, Hungary. FAU - Rojkovich, Bernadette AU - Rojkovich B AD - Buda Hospital of Hospitaller Brothers of St. John, Budapest, Hungary. FAU - Gati, Tamas AU - Gati T AD - Buda Hospital of Hospitaller Brothers of St. John, Budapest, Hungary. FAU - Simon, Melinda AU - Simon M AD - Department of Immunology, Eotvos Lorand University, Budapest, Hungary. FAU - Herincs, Zoltan AU - Herincs Z AD - Department of Immunology, Eotvos Lorand University, Budapest, Hungary. FAU - Sarmay, Gabriella AU - Sarmay G AD - Department of Immunology, Eotvos Lorand University, Budapest, Hungary. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140506 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (CPG-oligonucleotide) RN - 0 (Immunoglobulin G) RN - 0 (NF-kappa B) RN - 0 (Oligodeoxyribonucleotides) RN - 0 (Receptors, Antigen, B-Cell) RN - 0 (TLR9 protein, human) RN - 0 (Toll-Like Receptor 9) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - EC 2.7.11.25 (MAP kinase kinase kinase 7) SB - IM ECI - PLoS One. 2022 Mar 3;17(3):e0265030. PMID: 35239743 MH - B-Lymphocytes/*metabolism MH - Cell Proliferation/genetics MH - Humans MH - Immunoglobulin G/genetics MH - Lymphocyte Activation/genetics MH - MAP Kinase Kinase Kinases/*genetics/metabolism MH - Mitogen-Activated Protein Kinases/genetics/metabolism MH - NF-kappa B/genetics/metabolism MH - Oligodeoxyribonucleotides/genetics/metabolism MH - Receptors, Antigen, B-Cell/*genetics/metabolism MH - Signal Transduction/*genetics MH - Toll-Like Receptor 9/*genetics/metabolism MH - Tumor Necrosis Factor-alpha/genetics/metabolism PMC - PMC4011794 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/05/08 06:00 MHDA- 2015/01/13 06:00 PMCR- 2014/05/06 CRDT- 2014/05/08 06:00 PHST- 2013/09/25 00:00 [received] PHST- 2014/04/07 00:00 [accepted] PHST- 2014/05/08 06:00 [entrez] PHST- 2014/05/08 06:00 [pubmed] PHST- 2015/01/13 06:00 [medline] PHST- 2014/05/06 00:00 [pmc-release] AID - PONE-D-13-39423 [pii] AID - 10.1371/journal.pone.0096381 [doi] PST - epublish SO - PLoS One. 2014 May 6;9(5):e96381. doi: 10.1371/journal.pone.0096381. eCollection 2014.