title: TLR-mediated STAT3 and ERK activation controls IL-10 secretion by human B cells.
abstract: IL-10-producing B cells have a regulatory effect in various mouse models for immune-mediated disorders via secretion of IL-10, a potent immunoregulatory cytokine. However, currently, the signaling pathways that regulate IL-10 production in B cells are not well understood. Here, we show that TLR signaling, but not BCR activation or CD40 ligation, induces potent production of IL-10 in human B cells. We demonstrate that the activation of STAT3 and ERK is required for TLR-induced IL-10 production by B cells, since inhibition of STAT3 or ERK activation abrogates TLR-induced IL-10 production. We also uncover a novel function of the TLR-MyD88-STAT3 pathway in B cells, namely controlling IL-10 production, in addition to the known role for this pathway in antibody production. Furthermore, IFN-α, a member of the type I IFN family, differentially modulates TLR7/8- and TLR9-activated STAT3 and ERK in B cells, which provides an explanation for our findings that IFN-α enhances TLR7/8-induced, but not TLR9-induced IL-10 production. These results yield insights into the mechanisms by which TLR signaling regulates IL-10 production in B cells and how type I IFN modulates TLR-mediated IL-10 production by B cells, therefore providing potential targets to modulate the function of IL-10-producing B cells.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Bi-Sheng
authors.initials: BS
authors.lastname: Liu
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Cao
authors.forename: Tom W
authors.initials: TW
authors.lastname: Huizinga
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000502:physiology*; D051199:Toll-Like Receptor 7 / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D016898:Interferon-alpha; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: B10 cells; IL-10-producing B cells; Regulatory B cells; Toll-like receptor; Type I interferon