González-Ramos Reinaldo, Van Langendonckt Anne, Defrère Sylvie, Lousse Jean-Christophe, Mettlen Marcel, Guillet Alain, Donnez Jacques
Department of Gynecology, Université Catholique de Louvain, Brussels, Belgium.
Gynecol Obstet Invest. 2008;65(3):174-86. doi: 10.1159/000111148. Epub 2007 Nov 20.
In vitro studies suggest that the transcription factor nuclear factor-kappa B (NF-kappaB) is implicated in the transduction of proinflammatory signals in endometriosis. The aim of this study was to investigate the involvement of NF-kappaB and the processes regulated by NF-kappaB in the initial development of endometriotic lesionsin vivo.
Endometriosis was induced in nude mice by intraperitoneal injection of fluorescent-labeled menstrual endometrium. Two NF-kappaB inhibitors (BAY 11-7085 and SN-50) were injected intraperitoneally on days 0, 2 and 4 after endometriosis induction, and endometriotic lesions were recovered on day 5. Number, mass, fluorimetry and surface (morphometry) of endometriotic lesions were quantified. NF-kappaB activation, intercellular adhesion molecule (ICAM)-1 expression, cell proliferation and apoptosis were evaluated by immunohistochemical analyses and the TUNEL method.
Both NF-kappaB inhibitors induced a significant reduction in lesion development compared to control mice. NF-kappaB activation and ICAM-1 expression of endometriotic lesions were significantly reduced in treated mice, and cell proliferation was significantly reduced in BAY 11-7085-treated mice. Both inhibitors produced a significant increase in apoptosis of endometriotic lesions, as assessed by active caspase-3 immunostaining and the TUNEL method.
This study demonstrates, for the first time, that the NF-kappaB pathway is implicated in the development of endometriotic lesions in vivo and that NF-kappaB inhibition reduces ICAM-1 expression and cell proliferation, but increases apoptosis of endometriotic lesions, diminishing the initial development of endometriosis in an animal model.
体外研究表明，转录因子核因子-κB（NF-κB）参与子宫内膜异位症促炎信号的转导。本研究旨在探讨NF-κB及其调控过程在体内子宫内膜异位病变初始发展中的作用。
通过腹腔注射荧光标记的月经子宫内膜在裸鼠中诱导子宫内膜异位症。在诱导子宫内膜异位症后的第0、2和4天腹腔注射两种NF-κB抑制剂（BAY 11-7085和SN-50），并在第5天回收子宫内膜异位病变。对子宫内膜异位病变的数量、质量、荧光测定和表面（形态测定）进行量化。通过免疫组织化学分析和TUNEL法评估NF-κB激活、细胞间黏附分子（ICAM）-1表达、细胞增殖和凋亡。
与对照小鼠相比，两种NF-κB抑制剂均导致病变发展显著减少。在处理的小鼠中，子宫内膜异位病变的NF-κB激活和ICAM-1表达显著降低，在BAY 11-7085处理的小鼠中细胞增殖显著降低。通过活性半胱天冬酶-3免疫染色和TUNEL法评估，两种抑制剂均使子宫内膜异位病变的凋亡显著增加。
本研究首次证明，NF-κB途径参与体内子宫内膜异位病变的发展，NF-κB抑制降低ICAM-1表达和细胞增殖，但增加子宫内膜异位病变的凋亡，减少动物模型中子宫内膜异位症的初始发展。
