Wieser Fritz, Vigne Jean-Louis, Ryan Isabelle, Hornung Daniela, Djalali Schima, Taylor Robert N
Division of Gynecological Endocrinology and Reproductive Medicine, University of Vienna, Austria.
J Clin Endocrinol Metab. 2005 Dec;90(12):6441-7. doi: 10.1210/jc.2005-0972. Epub 2005 Sep 13.
The nuclear factor-kappaB (NF-kappaB) pathway is a critical mediator of RANTES (regulated on activation, normal T cell expressed and secreted) gene regulation and therefore represents a potential target for therapy of endometriosis-associated symptoms.
The objective of this study was to investigate the effects of the antiinflammatory drug sulindac on NF-kappaB activation, NF-kappaB-mediated gene expression, RANTES gene and protein expression in endometrial stromal cells isolated from women with endometriosis, and unaffected controls.
This was a clinical experimental study.
The study was conducted at a university hospital.
The inflammatory response in endometriosis is augmented by a 5-fold increased TNFalpha-induced RANTES secretion from ectopic endometriotic stromal cells, compared with normal endometrial stromal cells (P < 0.05). Western blot analysis revealed basal activation of NF-kappaB in endometriotic cells, which could be suppressed by sulindac. EMSAs showed that sulindac dramatically decreased NF-kappaB activation and diminished TNFalpha and IL-1beta-induced NF-kappaB DNA binding activity. Sulindac pretreatment resulted in a significant decrease in TNFalpha-induced luciferase activity of NF-kappaB response element and -477 bp RANTES promoter constructs in normal and endometriotic stromal cells. The addition of sulindac to IL-1beta- and TNFalpha-treated endometriotic stromal cells also resulted in a 4-fold inhibition of RANTES protein secretion (P < 0.05).
We have demonstrated that sulindac exerts strong antiinflammatory effects by suppression of NF-kappaB translocation, inhibition of NF-kappaB-mediated gene transcription, RANTES gene expression, and protein secretion in normal and endometriotic stromal cells. These results suggest that drugs targeting the NF-kappaB pathway may be beneficial in the treatment of endometriosis-associated symptoms.
核因子κB（NF-κB）信号通路是调节激活正常T细胞表达和分泌因子（RANTES）基因调控的关键介质，因此是治疗子宫内膜异位症相关症状的潜在靶点。
本研究旨在探讨抗炎药物舒林酸对从子宫内膜异位症患者及未受影响的对照者分离的子宫内膜基质细胞中NF-κB激活、NF-κB介导的基因表达、RANTES基因和蛋白表达的影响。
这是一项临床实验研究。
该研究在一家大学医院进行。
与正常子宫内膜基质细胞相比，异位子宫内膜基质细胞中肿瘤坏死因子α（TNFα）诱导的RANTES分泌增加了5倍，从而增强了子宫内膜异位症中的炎症反应（P<0.05）。蛋白质免疫印迹分析显示，子宫内膜异位细胞中NF-κB存在基础激活，而舒林酸可以抑制这种激活。电泳迁移率变动分析表明，舒林酸可显著降低NF-κB的激活，并减少TNFα和白细胞介素-1β（IL-1β）诱导的NF-κB与DNA的结合活性。舒林酸预处理导致正常和子宫内膜异位基质细胞中TNFα诱导的NF-κB反应元件和-477 bp RANTES启动子构建体的荧光素酶活性显著降低。在IL-1β和TNFα处理的子宫内膜异位基质细胞中添加舒林酸也导致RANTES蛋白分泌受到4倍的抑制（P<0.05）。
我们已经证明，舒林酸通过抑制正常和子宫内膜异位基质细胞中NF-κB易位、抑制NF-κB介导的基因转录、RANTES基因表达和蛋白分泌发挥强大的抗炎作用。这些结果表明，靶向NF-κB信号通路的药物可能对治疗子宫内膜异位症相关症状有益。
