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。涉及ECM周转的组织重塑受基质金属蛋白酶（MMPs）和MMPs的组织抑制剂（TIMPs）的联合作用调节。有报道称，子宫内膜异位症患者腹腔液中MMP-1的浓度升高，TIMP-1的浓度降低。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。本研究未发现子宫内膜异位症不孕患者腹腔液中MMP-1和TIMP-1的水平有任何差异。我们以前曾报道TNF-α通过诱导IL-8基因和蛋白的表达促进子宫内膜异位症间质细胞的增殖。我们推测TNF α可能通过激活核因子-κB（NF-κB）诱导凋亡细胞产生IL-S。Western blot分析和EMSA结果显示TNF α诱导凋亡基质细胞p-I κB表达和NF-κB活化。TNF α（0.1ng/ml）的加入使未用GnRH激动剂治疗的患者细胞中IL-8的蛋白和基因表达显著增加，而在用GnRHa治疗的患者细胞中未观察到这种表达。E2（10 μ M）的加入<-7>增强了IL-8的表达。而在接受GnRHa治疗的患者的细胞中，TNF α和E2未显示出任何显著影响。这些发现表明NF-κ B活化对于TNF α诱导的增生性基质细胞中IL-8的表达是关键的。目前的研究首次表明，GnRHa治疗通过减少TNF α诱导的NF-κB活化来减弱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.