Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor κB activation in mouse colonocytes

Background a Aims: 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 I kappa B alpha expression were determined by Western blot analysis. Nuclear transcription factor kappa B (NF-kappa B) 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-kappa B activation and nuclear translocation and the degradation of I kappa-B alpha were blocked by mesalamine. Conclusions: Mesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-kappa B. 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.