Abstract
The role of TNF-alpha in modulating intestinal crypt cell growth was examined, in comparison with EGF. Both significantly increased IEC-6 cell proliferation. Neither EGF nor TNF-alpha overcame the inhibitory effect on growth exerted by the tyrosine kinase inhibitor genistein. Immunoblots with phosphotyrosine antibodies showed increased tyrosine phosphorylation of IEC-6 cell proteins in response to EGF and TNF-alpha stimulation. TNF-alpha increased ERK1 and ERK2 MAPK phosphorylation. A MAPK assay confirmed the increased activity upon TNF-alpha stimulation. Selective inhibition of MAPK activation by PD98059 resulted in a dose dependent inhibition of TNF-alpha or EGF-induced IEC-6 cell growth. These findings suggest a role for TNF-alpha in the regulation of intestinal epithelial cell growth and that the mitogenic effect of TNF-alpha requires protein tyrosine phosphorylation and MAPK activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Cell Division / drug effects
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Cell Line
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Dose-Response Relationship, Drug
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Drug Interactions
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Epidermal Growth Factor / pharmacology*
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / physiology
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Flavonoids / pharmacology
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Genistein / pharmacology
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Intestinal Mucosa / cytology
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / growth & development*
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Jejunum / cytology
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Jejunum / drug effects
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Jejunum / growth & development*
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Protein Kinase Inhibitors*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Rats
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Flavonoids
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Protein Kinase Inhibitors
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Tumor Necrosis Factor-alpha
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Epidermal Growth Factor
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Genistein
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Protein-Tyrosine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one