title: TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK.
abstract: Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR-induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-κB.
authors.affiliation: The Francis Crick Institute, London NW1 1AT, England, UK.
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.affiliation: The Francis Crick Institute, London NW1 1AT, England, UK.
authors.forename: Josquin
authors.identifier: 0000-0002-6166-1588
authors.initials: J
authors.lastname: Nys
authors.affiliation: The Francis Crick Institute, London NW1 1AT, England, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Vanes
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage SG1 2NY, England, UK.
authors.forename: Nicholas
authors.identifier: 0000-0003-2263-3522
authors.initials: N
authors.lastname: Smithers
authors.affiliation: The Francis Crick Institute, London NW1 1AT, England, UK victor.t@crick.ac.uk.|Imperial College London, London W12 0NN, England, UK.
authors.forename: Victor L J
authors.identifier: 0000-0003-2439-0798
authors.initials: VLJ
authors.lastname: Tybulewicz
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D005260:Female; D008070:Lipopolysaccharides / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051057:Proto-Oncogene Proteins c-akt