TLR‐mediated STAT3 and ERK activation controls IL‐10 secretion by human B cells |
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| Authors: | Bi‐Sheng Liu Yonghao Cao Tom W. Huizinga David A. Hafler Rene E.M. Toes |
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| Affiliation: | 1. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands;2. Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA |
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| 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. |
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| Keywords: | B10 cells IL‐10‐producing B cells Regulatory B cells Toll‐like receptor Type I interferon |
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