TLR‐mediated STAT3 and ERK activation controls IL‐10 secretion by human B cells

• Published in: European journal of immunology Vol. 44; no. 7; pp. 2121 - 2129
• Main Authors: Liu, Bi‐Sheng, Cao, Yonghao, Huizinga, Tom W., Hafler, David A., Toes, Rene E.M.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.07.2014
• Subjects: B-Lymphocytes - immunology; B10 cells; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases - physiology; Humans; IL‐10‐producing B cells; Interferon-alpha - pharmacology; Interleukin-10 - biosynthesis; Lymphocyte receptors; Phosphorylation; Regulatory B cells; STAT3 Transcription Factor - physiology; Toll-Like Receptor 7 - physiology; Toll-Like Receptor 8 - physiology; Toll-Like Receptor 9 - physiology; Toll-Like Receptors - physiology; Toll‐like receptor; Type I interferon; Regulatory B cells; Type I interferon; IL-10-producing B cells; B10 cells; Toll-like receptor
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201344341

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.