TAK1 activation for cytokine synthesis and proliferation of endometriotic cells

Endometriosis causes pelvic pain and infertility in women of reproductive age. We explored TNF alpha-induced specific signaling pathways and gene expressions in endometriotic stromal cells (ESCs). Based on the data of the pathway specific cDNA array, we analyzed the role of TAK1, which is believed to work as a common mediator for NF-kappa B and MAPK pathways. Using the NF-kappa B pathway array, we found that TNF alpha upregulated ICAM-3, IL-6, IL-8, TAK1, JNK2, RelA, and TLR4 expressions. TNF alpha augmented the phosphorylation of TAK1. By transfection of TAK1 siRNA, TNF alpha-induced phosphorylation of I kappa B alpha, JNK1/2, and p38MAPK, as well as IL-6 or IL-8 expression, were repressed. TAK1 silencing in TNF alpha-pretreated ESCs caused a decrease in the proportion of cells in S-phase, and reduced TNF alpha-promoted BrdU incorporation. We provide the first evidence that TNF alpha and its downstream TAK1, which are key mediators for NF-kappa B and MAPK pathways, may be involved in the pathogenesis of endometriosis. (C) 2009 Elsevier Ireland Ltd. All rights reserved.