Mesalamine induces manganese superoxide dismutase in rat intestinal epithelial cell lines and in vivo.
Mesalamine (5-ASA) is effective in the treatment of inflammatory bowel diseases. However, the mechanisms of action of 5-ASA remain unclear. IEC-6 and IRD-98, nontransformed rat small intestinal epithelial cell lines, were used to examine the effect of 5-ASA on the expression of manganese superoxide dismutase (MnSOD). Rats were given 5-ASA enemas to determine the effect on colonic MnSOD expression. Treatment with 5-ASA at 0.02 or 2 mg/ml induced MnSOD mRNA levels 2.67-fold or 5.66-fold, respectively. Inhibition of 5-lipoxygenase activating protein with MK-886 or cyclooxygenase with indomethacin did not influence the level of MnSOD mRNA. Nuclear run-on experiments demonstrated an increase in de novo transcription following treatment with 5-ASA. MnSOD protein levels were induced 2-fold at 24 h and 4.23-fold at 48 h following treatment with 1 mg/ml 5-ASA. 5-ASA increased MnSOD 1.7-fold in vivo. Pretreatment with 5-ASA significantly protected IRD-98 cells from tumor necrosis factor-alpha cytotoxicity. This is the first example of transcriptional gene regulation by 5-ASA. The induction of MnSOD by 5-ASA may contribute to the therapeutic mechanism of 5-ASA.
Valentine
J F
JF
Malcom Randall Veterans Affairs Medical Center and the Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida 32610, USA. valenjf@medicine.ufl.edu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D019804:Mesalamine / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D002722:Chlorobenzenes
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003513:Cycloheximide; D016861:Cyclooxygenase Inhibitors; D003609:Dactinomycin; D016166:Free Radical Scavengers; D007211:Indoles; D007213:Indomethacin; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D019804:Mesalamine; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; C060893:MK-886; D002722:Chlorobenzenes