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

Background a Aims: Derivatives of 5-aminosalicylic acid (mesalamine) repres ent a mainstay in inflammatory bowel disease therapy, yet the precise mecha nism 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 tra nsduction and proliferation in intestinal epithelial cells. Methods: Young adult mouse colon cells were studied with TNF-alpha, epidermal growth facto r, 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. N uclear transcription factor kappa B (NF-kappa B) nuclear translocation was determined by confocal laser immunofluorescent microscopy. Results: The ant iproliferative effects of TNF-alpha were blocked by mesalamine. TNF-alpha a nd 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 degradat ion of I kappa-B alpha were blocked by mesalamine. Conclusions: Mesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell prolifera tion and activation of MAP kinase and NF-kappa B. Therefore, it may functio n as a therapeutic agent based on its ability to disrupt critical signal tr ansduction events in the intestinal cell necessary for perpetuation of the chronic inflammatory state.