Role of matrix met alloprot einases and cytokines in the development of endometriosis

认为细胞外基质（ECM）重构与子宫内膜异位症的发生发展有关。涉及ECM转换的组织重塑是由基质金属蛋白酶（MMPs）和基质金属蛋白酶的组织抑制剂（TIMPs）的联合作用调节的。据报道，子宫内膜异位症患者腹膜液中MMP-1浓度升高，TIMP-1浓度降低。本研究旨在探讨MMPs和TIMPs在子宫内膜异位症发生中的可能作用。然而，在这项研究中，我们没有发现有和没有子宫内膜异位症的不孕症患者腹膜液中MMP-1和TIMP-1的水平有任何差异。我们之前报道过TNF a通过诱导IL-8基因和蛋白表达促进子宫内膜异位症基质细胞的增殖。我们假设TNF a可能通过活化核因子-κB （NF-κB）诱导子宫内膜异位症细胞产生IL-S。Western blot和EMSA分析显示，TNF α可诱导子宫内膜异位症基质细胞p-I κB的表达和NF-κB的活化。添加TNF α (0.1ng/ml)可显著提高未使用GnRH激动剂治疗的患者细胞中IL-8蛋白和基因的表达，但在GnRH激动剂治疗的患者细胞中未观察到这种表达。E2 （10^<-7>M）的加入增强了IL-8的表达。然而，在接受GnRHa治疗的患者细胞中，TNF α和E2没有表现出明显的影响。这些发现表明，NF-κ B活化对TNF α-诱导的IL-8在子宫内膜异位症基质细胞中的表达至关重要。本研究首次发现GnRHa通过降低TNF α-诱导的NF-κB活化来降低IL-8的表达。

It is believed that the extracellular matrix (ECM) remodeling is relevant to the development and the progression of endometriosis. Tissue remodeling involving ECM turnover is regulated by the combined action of matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs). It has been reported that the concentration of MMP-1 is increased and that of TIMP-1 is decreased in peritoneal fluid of patients with endometriosis. The present study was undertaken to investigate the possible role of MMPs and TIMPs in the development of endometriosis. In this study, however, we did not find any difference in the levels of MMP-1 and TIMP-1 in peritoneal fluid between infertile patients with and without endometriosis.We previously reported that TNF a promoted proliferation of endometriotic stromal cells by inducing IL-8 gene and protein expression. We hypothesize that TNF a may induce IL-S production in endometriotic cells through nuclear factor-κB (NF-κB) activation. Western blot analyses and EMSA revealed that incubation with TNF α induced the expression of p-I κB and activation of NF-κB in endometriotic stromal cells. The addition of TNF α (0.1ng/ml) significantly increased protein and gene expression of IL-8 in the cells of patients without GnRH agonist treatment, but this expression was not observed in the cells of patients with GnRHa. The addition of E2 (10^<-7>M) enhanced the expression of IL-8. However, in the cells of patients who received GnRHa treatment, TNF α and E2 did not show any significant effect. These findings demonstrate that NF-κ B activation is critical for TNF α-induced IL-8 expression in endometriotic stromal cells. The current study showed for the first time that GnRHa treatment attenuated the expression of IL-8 by reducing TNF α-induced NF-κB activation.