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

细胞外基质(ECM)重塑与子宫内膜异位症的发生发展密切相关。基质金属蛋白酶(MMPs)和基质金属蛋白酶组织抑制因子(TIMPs)共同作用调节细胞外基质代谢的组织重塑。已有研究表明，子宫内膜异位症患者腹腔液中基质金属蛋白酶-1浓度升高，而基质金属蛋白酶-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发展中的可能作用。然而，在本研究中，我们没有发现患有和不患有子宫内膜异位症的不孕症患者腹腔液中的MMP-1和TIMP-1水平有任何差异。我们先前的报道是通过诱导IL-8基因和蛋白的表达来促进子宫内膜异位间质细胞的增殖。我们推测，肿瘤坏死因子α可能通过核因子-κB(NF-κB)激活诱导异位内膜细胞产生IL-S。Western印迹分析和EMSA分析显示，与肿瘤坏死因子α孵育可诱导异位内膜基质细胞p-IκB的表达和NF-κB的激活。在未用促性腺激素释放激素激动剂治疗的患者细胞中，加入肿瘤坏死因子α(0.1 ng/ml)后，IL-8的蛋白和基因表达显著增加，而在促性腺激素释放激素激动剂治疗的患者细胞中未观察到这种表达。加入E_2(10^&lt；-7&gt；M)可增强IL-8的表达。然而，在接受GnRHa治疗的患者的细胞中，肿瘤坏死因子α和E2没有显示出任何显著的影响。这些结果表明，核因子-κB的激活在肿瘤坏死因子α诱导的子宫内膜间质细胞IL-8的表达中起关键作用。目前的研究首次表明，GnRHa治疗通过减少肿瘤坏死因子α诱导的NF-κB的激活来减弱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.