QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.042176v1 73/5/1394    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Grund, E. M. Articles by Palmer, S. S. PubMed PubMed Citation Articles by Grund, E. M. Articles by Palmer, S. S.

Tumor Necrosis Factor- Regulates Inflammatory and Mesenchymal Responses via Mitogen-Activated Protein Kinase Kinase, p38, and Nuclear Factor B in Human Endometriotic Epithelial Cells

EMD-Serono Research Institute, Rockland, Massachusetts (E.M.G., D.K., C.A.T., S.N., S.S.P.); and Humangenetik fuer Biologen, Johann Wolfgang Goethe-Universitat, Frankfurt, Germany (A.Z., A.S.-P.)

Tumor necrosis factor (TNF)- is central to the endometriotic disease process. TNF- receptor signaling regulates epithelial cell secretion of inflammation and invasion mediators. Because epithelial cells are a disease-inducing component of the endometriotic lesion, we explored the response of 12Z immortalized human epithelial endometriotic cells to TNF-. This report reveals the impact of disruption of established TNF--induced signaling cascades on the expression of biomarkers of inflammation and epithelial-mesenchymal transition (EMT) from endometriotic epithelial cells. Note that we show the molecular potential of soluble TNF-R1 [TNF binding protein (TBP)] and a panel of small molecule kinase inhibitors to block endometriotic gene expression directly. The TNF- receptor is demonstrated to signal through IB kinase complex (IKK) 2 > IB > nuclear factor B, extracellular signal-regulated kinase > mitogen-activated protein kinase kinase (MEK), p38, and phosphatidylinositol 3-kinase (PI3K) > Akt1/2. TNF- induces the expression of transcripts for inflammatory mediators interleukin (IL)-6, IL-8, regulated on activation normal T cell expressed and secreted, TNF-, granulocyte macrophage-colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)-1 and also invasion mediators matrix metalloproteinase (MMP)-7, MMP-9, and intracellular adhesion molecule-1. Indeed, TBP inhibits the TNF--induced expression of all the above endometriotic genes in 12Z endometriotic epithelial cells. The secretion of IL-6, IL-8, GMCSF, and MCP-1 by TNF- is blocked by TBP. Interestingly, MEK, p38, and IKK inhibitors block TNF--induced IL-8, IL-6, and GM-CSF secretion and 12z invasion, whereas the PI3K inhibitors do not. The only inhibitor to block MCP-1 expression is the p38 inhibitor. Last, TBP, MEK inhibitor, or p38 inhibitor also block cell surface expression of N-cadherin, a marker of mesenchymal cells. Taken together, these results demonstrate that interruption of TNF--induced signaling pathways in human endometriotic epithelial cells results in decreased expression and secretion of biomarkers for inflammation, EMT, and disease progression.

Address correspondence to: Stephen S. Palmer, EMD-Serono Research Institute, One Technology Place, Rockland, MA 02190. E-mail: stephen.palmer{at}emdserono.com