title: Syk is indispensable for CpG-induced activation and differentiation of human B cells.
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.
authors.affiliation: MTA-ELTE Immunology Research Group, Budapest, Hungary.
authors.forename: Mariann
authors.initials: M
authors.lastname: Kremlitzka
authors.forename: Bernadett
authors.initials: B
authors.lastname: Mácsik-Valent
authors.forename: Anna
authors.initials: A
authors.lastname: Erdei
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000072377:Syk Kinase; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D034741:RNA, Small Interfering; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases