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Research ArticleArticle

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

Eric M. Grund, David Kagan, Cam Anh Tran, Andreas Zeitvogel, Anna Starzinski-Powitz, Selvaraj Nataraja and Stephen S. Palmer
Molecular Pharmacology May 2008, 73 (5) 1394-1404; DOI: https://doi.org/10.1124/mol.107.042176
Eric M. Grund
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.)
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David Kagan
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.)
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Cam Anh Tran
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.)
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Andreas Zeitvogel
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.)
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Anna Starzinski-Powitz
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.)
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Selvaraj Nataraja
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.)
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Stephen S. Palmer
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.)
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Abstract

Tumor necrosis factor (TNF)-α is central to the endometriotic disease process. TNF-α 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-α. This report reveals the impact of disruption of established TNF-α-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-α receptor is demonstrated to signal through IκB kinase complex (IKK) 2 > IκB > nuclear factor κB, extracellular signal-regulated kinase > mitogen-activated protein kinase kinase (MEK), p38, and phosphatidylinositol 3-kinase (PI3K) > Akt1/2. TNF-α induces the expression of transcripts for inflammatory mediators interleukin (IL)-6, IL-8, regulated on activation normal T cell expressed and secreted, TNF-α, 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-α-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-α is blocked by TBP. Interestingly, MEK, p38, and IKK inhibitors block TNF-α-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-α-induced signaling pathways in human endometriotic epithelial cells results in decreased expression and secretion of biomarkers for inflammation, EMT, and disease progression.

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Molecular Pharmacology: 73 (5)
Molecular Pharmacology
Vol. 73, Issue 5
1 May 2008
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Research ArticleArticle

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

Eric M. Grund, David Kagan, Cam Anh Tran, Andreas Zeitvogel, Anna Starzinski-Powitz, Selvaraj Nataraja and Stephen S. Palmer
Molecular Pharmacology May 1, 2008, 73 (5) 1394-1404; DOI: https://doi.org/10.1124/mol.107.042176

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Research ArticleArticle

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

Eric M. Grund, David Kagan, Cam Anh Tran, Andreas Zeitvogel, Anna Starzinski-Powitz, Selvaraj Nataraja and Stephen S. Palmer
Molecular Pharmacology May 1, 2008, 73 (5) 1394-1404; DOI: https://doi.org/10.1124/mol.107.042176
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