Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells.
Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells.
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DOI：
10.1038/mi.2015.131
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发表时间：
2016-09
影响因子：
8
通讯作者：
Sheldon IM
中科院分区：
文献类型：
--
作者：
Cronin JG;Kanamarlapudi V;Thornton CA;Sheldon IM
白介素6(IL-6)通过白介素6受体(IL6R)和信号转导及转录激活子3(STAT3)发挥作用，一旦细菌感染消失，就能限制中性粒细胞的募集。牛子宫内膜炎是一种典型的粘膜疾病，其特征是产后革兰氏阴性细菌感染后持续的中性粒细胞浸润和中性粒细胞趋化因子IL-6和IL-8的升高。本研究检测了IL-6R/STAT3信号通路对原代子宫内膜细胞在短期或长期暴露于来自革兰氏阴性菌的脂多糖(LPS)后产生IL-8的影响。STAT3的酪氨酸磷酸化是DNA结合和表达特定靶基因所必需的。免疫印迹显示，急性内毒素暴露可抑制子宫内膜细胞中STAT3的结构性酪氨酸磷酸化。在脂多糖作用24 h后，STAT3恢复到酪氨酸磷酸化状态，提示Toll样受体4(TLR4)与IL6R/STAT3信号通路之间存在串扰。针对IL6R的短干扰RNA抑制了内毒素诱导的IL-6和IL-8的积聚，证实了这一点。此外，由于IL-6和IL-8在间质细胞中的积累依赖于细胞因子信号转导抑制物STAT3和Src激酶信号，而不是上皮细胞，因此存在不同的子宫内膜细胞反应。总之，通过IL6R的正反馈放大了内毒素诱导的子宫内膜中IL-6和IL-8的产生。这些发现提供了一种机制上的洞察，即在细菌感染期间，产后子宫内膜中IL-6浓度升高是如何导致显著和持续的中性粒细胞渗透的。
Interleukin 6 (IL-6), acting via the IL-6 receptor (IL6R) and signal transducer and activator of transcription-3 (STAT3), limits neutrophil recruitment once bacterial infections are resolved. Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and elevated IL-6 and IL-8, a neutrophil chemoattractant, following postpartum Gram-negative bacterial infection. The present study examined the impact of the IL6R/STAT3 signaling pathway on IL-8 production by primary endometrial cells in response to short- or long-term exposure to lipopolysaccharide (LPS) from Gram-negative bacteria. Tyrosine phosphorylation of STAT3 is required for DNA binding and expression of specific targets genes. Immunoblotting indicated constitutive tyrosine phosphorylation of STAT3 in endometrial cells was impeded by acute exposure to LPS. After 24 h exposure to LPS, STAT3 returned to a tyrosine phosphorylated state, indicating cross-talk between the Toll-like receptor 4 (TLR4) and the IL6R/STAT3 signaling pathways. This was confirmed by short interfering RNA targeting the IL6R, which abrogated the accumulation of IL-6 and IL-8, induced by LPS. Furthermore, there was a differential endometrial cell response, as the accumulation of IL-6 and IL-8 was dependent on STAT3, suppressor of cytokine signaling 3, and Src kinase signaling in stromal cells, but not epithelial cells. In conclusion, positive feedback through the IL6R amplifies LPS-induced IL-6 and IL-8 production in the endometrium. These findings provide a mechanistic insight into how elevated IL-6 concentrations in the postpartum endometrium during bacterial infection leads to marked and sustained neutrophil infiltration.