Cohen Marie, Meisser Arielle, Haenggeli Luise, Bischof Paul
Department of Obstetrics and Gynaecology, Maternity, Hormone Laboratory, University of Geneva, Boulevard de la Cluse, Switzerland.
Mol Hum Reprod. 2006 Apr;12(4):225-32. doi: 10.1093/molehr/gal023. Epub 2006 Mar 6.
The aim of this article was to investigate the signalling pathways involved in metalloproteinase-9 (MMP-9) expression induced by tumour necrosis factor-alpha (TNF-alpha) in first-trimester trophoblastic cells. TNF-alpha-induced MMP-9 expression, secretion and activity were completely blocked by stress-activated protein kinase/jun kinase (SAPK/JNK) and Erk inhibitors (SP600 125 and U0126 respectively) but not by p38 mitogen-activated protein kinase (MAPK) inhibitors (SB203 580 and SB202 190). Stimulation of HIPEC 65 cells with TNF-alpha caused phosphorylation of JNK and extracellular signal-regulated kinase 1/2 (Erk1/2), with a peak after 20 min of treatment. Transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1)-binding site were identified as the cis-elements involved in TNF-alpha activation as determined by electromobility shift assays. TNF-alpha-induced transactivation of NF-kappaB was inhibited by U0126, whereas TNF-alpha-induced transactivation of AP-1 was inhibited by SP600 125. Taken together, these results indicate that in trophoblastic cells, TNF-alpha probably activates two different pathways leading to MMP-9 expression: (a) Erk1/2 pathway which in turn initiates NF-kappaB activation and (b) SAPK/JNK pathway that activates AP-1.
本文旨在研究早孕滋养层细胞中肿瘤坏死因子-α（TNF-α）诱导金属蛋白酶-9（MMP-9）表达所涉及的信号通路。TNF-α诱导的MMP-9表达、分泌及活性被应激激活蛋白激酶/ Jun激酶（SAPK/JNK）和Erk抑制剂（分别为SP600 125和U0126）完全阻断，但未被p38丝裂原活化蛋白激酶（MAPK）抑制剂（SB203 580和SB202 190）阻断。用TNF-α刺激HIPEC 65细胞导致JNK和细胞外信号调节激酶1/2（Erk1/2）磷酸化，处理20分钟后达到峰值。通过电泳迁移率变动分析确定，转录因子核因子-κB（NF-κB）和活化蛋白1（AP-1）结合位点为参与TNF-α激活的顺式元件。U0126抑制TNF-α诱导的NF-κB反式激活，而SP600 125抑制TNF-α诱导的AP-1反式激活。综上所述，这些结果表明，在滋养层细胞中，TNF-α可能激活两条导致MMP-9表达的不同途径：（a）Erk1/2途径，其继而启动NF-κB激活；（b）激活AP-1的SAPK/JNK途径。
