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

基质金属同种异体蛋白酶和细胞因子在子宫内膜异位症发生中的作用

基本信息

批准号：
14370534
负责人：
TERAKAWA Naoki
金额：
$ 3.71万
依托单位：
Tottori University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370534/
关键词：
Endometriosis Development and progression Endometriotic stromal cells Cytokine TNFα IL-8 Nuclear fact or-κB Estrogen GnRH agonist 間質細胞発生・進展サイトカインファミリー TNF-α 遺伝子発現

项目摘要

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.

人们认为细胞外基质（ECM）重塑与子宫内膜异位症的发生和进展有关。涉及 ECM 更新的组织重塑受到基质金属蛋白酶 (MMP) 和 MMP 组织抑制剂 (TIMP) 联合作用的调节。有报道子宫内膜异位症患者腹腔液中MMP-1浓度升高，TIMP-1浓度降低。本研究旨在调查 MMP 和 TIMP 在子宫内膜异位症发展中的可能作用。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患者腹腔液中MMP-1和TIMP-1的水平有任何差异。我们之前报道过TNFa通过诱导IL-8基因和蛋白表达来促进子宫内膜异位基质细胞的增殖。我们假设 TNF a 可能通过核因子-κB (NF-κB) 激活诱导子宫内膜异位细胞产生 IL-S。 Western blot 分析和 EMSA 显示，与 TNF α 孵育可诱导子宫内膜异位基质细胞中 p-I κB 的表达和 NF-κB 的激活。添加TNFα(0.1ng/ml)显着增加未经GnRH激动剂治疗的患者细胞中IL-8的蛋白和基因表达，但在GnRHa患者的细胞中未观察到这种表达。 E2(10^-7M)的添加增强了IL-8的表达。然而，在接受GnRHa治疗的患者细胞中，TNFα和E2并没有表现出任何明显的作用。这些发现表明，NF-κ B 激活对于子宫内膜异位基质细胞中 TNF α 诱导的 IL-8 表达至关重要。目前的研究首次表明，GnRHa 治疗通过减少 TNF α 诱导的 NF-κB 激活来减弱 IL-8 的表达。