title: TGFβ activated kinase 1 (TAK1) at the crossroad of B cell receptor and Toll-like receptor 9 signaling pathways in human B cells.
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 NFκB 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.
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Dániel
authors.initials: D
authors.lastname: Szili
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bankó
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Eszter Angéla
authors.initials: EA
authors.lastname: Tóth
authors.affiliation: Buda Hospital of Hospitaller Brothers of St. John, Budapest, Hungary; Department of Rheumatology, Semmelweis University, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Nagy
authors.affiliation: Buda Hospital of Hospitaller Brothers of St. John, Budapest, Hungary.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Rojkovich
authors.affiliation: Buda Hospital of Hospitaller Brothers of St. John, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Gáti
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Melinda
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hérincs
authors.affiliation: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sármay
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D007074:Immunoglobulin G; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D011947:Receptors, Antigen, B-Cell; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C408982:CPG-oligonucleotide; C495371:TLR9 protein, human