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Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells.
Mol Pharmacol. 2008 May; 73(5):1394-404.MP

Abstract

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

Authors+Show Affiliations

EMD-Serono Research Institute, One Technology Place, Rockland, MA 02190, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18252806

Citation

Grund, Eric M., et al. "Tumor Necrosis Factor-alpha Regulates Inflammatory and Mesenchymal Responses Via Mitogen-activated Protein Kinase Kinase, P38, and Nuclear Factor kappaB in Human Endometriotic Epithelial Cells." Molecular Pharmacology, vol. 73, no. 5, 2008, pp. 1394-404.
Grund EM, Kagan D, Tran CA, et al. Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. Mol Pharmacol. 2008;73(5):1394-404.
Grund, E. M., Kagan, D., Tran, C. A., Zeitvogel, A., Starzinski-Powitz, A., Nataraja, S., & Palmer, S. S. (2008). Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. Molecular Pharmacology, 73(5), 1394-404. https://doi.org/10.1124/mol.107.042176
Grund EM, et al. Tumor Necrosis Factor-alpha Regulates Inflammatory and Mesenchymal Responses Via Mitogen-activated Protein Kinase Kinase, P38, and Nuclear Factor kappaB in Human Endometriotic Epithelial Cells. Mol Pharmacol. 2008;73(5):1394-404. PubMed PMID: 18252806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. AU - Grund,Eric M, AU - Kagan,David, AU - Tran,Cam Anh, AU - Zeitvogel,Andreas, AU - Starzinski-Powitz,Anna, AU - Nataraja,Selvaraj, AU - Palmer,Stephen S, Y1 - 2008/02/05/ PY - 2008/2/7/pubmed PY - 2008/5/7/medline PY - 2008/2/7/entrez SP - 1394 EP - 404 JF - Molecular pharmacology JO - Mol Pharmacol VL - 73 IS - 5 N2 - Tumor necrosis factor (TNF)-alpha is central to the endometriotic disease process. TNF-alpha 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-alpha. This report reveals the impact of disruption of established TNF-alpha-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-alpha receptor is demonstrated to signal through IkappaB kinase complex (IKK) 2 > IkappaB > nuclear factor kappaB, extracellular signal-regulated kinase > mitogen-activated protein kinase kinase (MEK), p38, and phosphatidylinositol 3-kinase (PI3K) > Akt1/2. TNF-alpha induces the expression of transcripts for inflammatory mediators interleukin (IL)-6, IL-8, regulated on activation normal T cell expressed and secreted, TNF-alpha, 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-alpha-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-alpha is blocked by TBP. Interestingly, MEK, p38, and IKK inhibitors block TNF-alpha-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-alpha-induced signaling pathways in human endometriotic epithelial cells results in decreased expression and secretion of biomarkers for inflammation, EMT, and disease progression. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/18252806/Tumor_necrosis_factor_alpha_regulates_inflammatory_and_mesenchymal_responses_via_mitogen_activated_protein_kinase_kinase_p38_and_nuclear_factor_kappaB_in_human_endometriotic_epithelial_cells_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18252806 DB - PRIME DP - Unbound Medicine ER -