Exploring the mechanism of cell proliferation and the novel molecular target therapy of endometriosis

我们以前报道过子宫内膜异位症患者腹腔液中的促炎细胞因子，如肿瘤坏死因子（TNF）-α和白细胞介素（IL）-8升高。此外，TNFα通过激活NF-κB增强卵巢上皮性癌（ESCs）的促有丝分裂活性并上调IL-8的表达。子宫内膜异位组织的生长依赖于卵巢类固醇激素，特别是雌激素。TNFα通过雌激素作用诱导IL-8的产生可能参与了子宫内膜异位症发生发展的分子机制，子宫内膜异位症患者卵巢巧克力囊肿衬里是异位组织的来源。TNFα和E2联合作用可通过NFκB途径促进细胞增殖和IL-8表达。相反，P4、地诺孕素或达那唑减弱NFκB活化和IL-8表达。这些数据表明激素治疗控制子宫内膜异位症的可能分子机制。接下来，我们进行了关于GnRH拮抗剂醋酸西曲瑞克的临床试验。通过对子宫内膜异位症患者血清IL-6、IL-8水平的分析，发现西曲瑞克治疗子宫内膜异位症后，患者疼痛评分及临床症状评分均明显降低。西曲瑞克治疗子宫内膜异位症可显著降低血清IL-6水平，本研究首次证实GnRH拮抗剂西曲瑞克可改善临床症状，降低血清IL-6水平，提示该药可能对子宫内膜异位症有治疗作用。

We previous reported that the proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-8 are elevated in the peritoneal fluid of women with endometriosis. In addition, TNFα enhances the mitogenic activity and upregulates IL-8 expression through NF-κB activation in endometriotic stromal cells from ovarian endometrioma (ESCs). Endometriotic tissue growth depends on ovarian steroid hormones, especially estrogen. TNFα induced-IL-8 production via estrogen action may be involved in the molecular mechanisms for development of endometriosis.The chocolate cysts linings of the ovaries of patients with endometriosis were the source of endometriotic tissues. Adding TNFα together with E2 markedly enhanced cell proliferation and IL-8 expression via NFκB pathway. In contrast, P4, dienogest, or danazol attenuated NFκB activation and IL-8 expression. These data suggest that a possible molecular mechanism of hormone therapy for controlling the growth of endometriosis.Next, we performed the clinical trial regarding a GnRH antagonist, Cetrorelix Acetate. We analyzed that serum IL-6 and IL-8 concentration of the patients with endometriosis.By the injection of Cetrorelix to the patients, the score of pain and of clinical symptoms were decreased. Cetrorelix therapy significantly suppressed the serum IL-6 concentration.We demonstrated for the first time that a GnRH antagonist, Cetrorelix improved the clinical symptoms and decreased serum IL-6 concentration, suggesting this novel drug may be effective for the therapy of endometriosis.