TLR-mediated STAT3 and ERK activation controls IL-10 secretion by human B cells
TLR-mediated STAT3 and ERK activation controls IL-10 secretion by human B cells
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DOI：
10.1002/eji.201344341
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发表时间：
2014-07-01
影响因子：
5.4
通讯作者：
Toes, Rene E. M.
中科院分区：
文献类型：
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作者：
Liu, Bi-Sheng;Cao, Yonghao;Toes, Rene E. M.
产生IL-10的B细胞通过分泌IL-10（一种有效的免疫调节细胞因子）在免疫介导的疾病的各种小鼠模型中具有调节作用。然而，目前，调节B细胞中IL-10产生的信号传导途径还不清楚。在这里，我们发现TLR信号，而不是BCR激活或CD 40连接，诱导人B细胞中IL-10的有效产生。我们证明，活化的STAT 3和ERK的TLR诱导的IL-10的生产所需的B细胞，因为抑制STAT 3或ERK的活化废除TLR诱导的IL-10的生产。我们还发现了TLR-MyD 88-STAT 3途径在B细胞中的新功能，即控制IL-10的产生，除了该途径在抗体产生中的已知作用之外。此外，IFN-α，I型IFN家族的成员，在B细胞中差异性地调节TLR 7/8和TLR 9激活的STAT 3和ERK，这为我们的发现IFN-α增强TLR 7/8诱导的IL-10产生而非TLR 9诱导的IL-10产生提供了解释。这些结果产生了对TLR信号调节B细胞中IL-10产生的机制以及I型IFN如何调节B细胞的TLR介导的IL-10产生的见解，因此提供了调节产生IL-10的B细胞的功能的潜在靶点。
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-alpha, 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-alpha 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.