TLR4 Activation Promotes the Secretion of IL-8 Which Enhances the Invasion and Proliferation of Endometrial Stromal Cells in an Autocrine Manner via the FAK Signal Pathway
TLR4 Activation Promotes the Secretion of IL-8 Which Enhances the Invasion and Proliferation of Endometrial Stromal Cells in an Autocrine Manner via the FAK Signal Pathway
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TLR4激活促进IL-8的分泌，通过FAK信号通路以自分泌方式增强子宫内膜基质细胞的侵袭和增殖
DOI：
10.1111/aji.12425
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发表时间：
2015-12-01
影响因子：
3.6
通讯作者：
Li, Da-jin
中科院分区：
文献类型：
--
作者：
Luo, Xue-zhen;Zhou, Wen-jie;Li, Da-jin
慢性炎症对子宫内膜异位症的发生很重要，但其分子机制尚不清楚。TLR4不仅在免疫细胞上表达，也存在于人子宫内膜中，其调控可能对子宫内膜异位症的发病机制至关重要。本研究采用免疫组化方法分析了TLR4在正常、异位和异位子宫内膜中的表达。通过细胞内Western法检测子宫内膜基质细胞（ESCs）中关键分子的表达。采用Matrigel侵袭试验评估子宫内膜异位症患者异位ESCs的侵袭性。采用BrdU法评估CXCL8对体外培养的ESCs增殖的影响。结果发现TLR4在异位子宫内膜中的表达高于正常子宫内膜，其中异位组织的表达水平最高。TLR4激活通过激活p38/ERK而非JNK和NK-kappa B信号通路刺激内皮细胞中IL-8的分泌及其受体CXCR1的表达。IL-8可通过FAK信号通路增强ESCs的侵袭和增殖，这些作用可被抗cxcl8中和抗体或FAK抑制剂所消除。
ProblemChronic inflammation is important for the occurrence of endometriosis, but the molecular mechanisms are still poorly understood. TLR4 is not only expressed on immune cells but is also present in the human endometrium, and its regulation might be crucial for the pathogenesis of endometriosis.Method of studyIn this study, the expression of TLR4 in normal, eutopic endometrium, and ectopic tissues was analyzed by immunohistochemistry. The expression of the key molecules in endometrial stromal cells (ESCs) was assessed by in-cell Western assays. The invasion of eutopic ESCs from patients with endometriosis was evaluated by Matrigel invasion assay. The effects of CXCL8 on the proliferation of ESCs in vitro were assessed using BrdU assays.ResultsWe found that the expression of TLR4 is higher in the eutopic endometrium than the normal endometrium and that ectopic tissue had the highest level of expression. TLR4 activation stimulated IL-8 secretion and the expression of its receptor CXCR1 in ESCs by activating p38/ERK, but not JNK and NK-kappa B signal pathways. IL-8 could enhance the invasion and proliferation of ESCs through the FAK signal pathway, and these effects could be abolished by an anti-CXCL8 neutralizing antibody or by a FAK inhibitor.