Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor kappaB activation in mouse colonocytes.
OBJECTIVE
Derivatives of 5-aminosalicylic acid (mesalamine) represent a mainstay in inflammatory bowel disease therapy, yet the precise mechanism of their therapeutic action is unknown. Because tumor necrosis factor (TNF)-alpha is important in the pathogenesis of inflammatory bowel disease, we investigated the effect of mesalamine on TNF-alpha-regulated signal transduction and proliferation in intestinal epithelial cells.


METHODS
Young adult mouse colon cells were studied with TNF-alpha, epidermal growth factor, or ceramide in the presence or absence of mesalamine. Proliferation was studied by hemocytometry. Mitogen-activated protein (MAP) kinase activation and IkappaBalpha expression were determined by Western blot analysis. Nuclear transcription factor kappaB (NF-kappaB) nuclear translocation was determined by confocal laser immunofluorescent microscopy.


RESULTS
The antiproliferative effects of TNF-alpha were blocked by mesalamine. TNF-alpha and ceramide activation of MAP kinase were inhibited by mesalamine, whereas epidermal growth factor activation of MAP kinase was unaffected. TNF-alpha-stimulated NF-kappaB activation and nuclear translocation and the degradation of Ikappa-Balpha were blocked by mesalamine.


CONCLUSIONS
Mesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-kappaB. Therefore, it may function as a therapeutic agent based on its ability to disrupt critical signal transduction events in the intestinal cell necessary for perpetuation of the chronic inflammatory state.
Kaiser
G C
GC
Division of Gastroenterology and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Yan
F
F
Polk
D B
DB
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000502:physiology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019804:Mesalamine / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D002518:Ceramides; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019804:Mesalamine; D004815:Epidermal Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases