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Antioxidant Properties of Mesalamine in Colitis Inhibit Phosphoinositide 3-Kinase Signaling in Progenitor Cells

Managlia, Elizabeth PhD; Katzman, Rebecca B. PhD; Brown, Jeffrey B. MD; Barrett, Terrence A. MD

Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e318297d741
Original Basic Science Articles
Abstract

Background: Mesalamine, 5-aminosalicylic acid (5-ASA), is a potent antioxidant and is known to enhance peroxisome proliferator–activated receptor γ activity in the intestine. Our previous studies suggested reduced Phosphoinositide 3-Kinase (PI3K)/β-catenin signaling as a mechanism for 5-ASA chemoprevention in chronic ulcerative colitis (CUC). We now hypothesize that 5-ASA mediates changes in intestinal epithelial cell (IEC) reactive oxygen species during colitis to affect phosphatase and tensin homolog (PTEN), PI3K, and β-catenin signaling.

Methods: Here, we examined effects of 5-ASA on oxidant-induced cell signaling pathways in HT-29 cells, IECs from mice, and biopsy tissue from control and CUC patients. Samples were selected to control for inflammation between untreated and 5-ASA–treated CUC patients.

Results: Direct evaluation of IEC in H2O2-stimulated whole colonic crypts indicated that 5-ASA reduces reactive oxygen species levels in lower crypt IECs where long-lived progenitor cells reside. Analysis of biopsies from patient samples revealed that 5-ASA increases expression of the antioxidant catalase in CUC patients. Also, 5-ASA increased nuclear peroxisome proliferator–activated receptor γ protein and target gene expression. Data showed 5-ASA–induced peroxisome proliferator–activated receptor γ DNA binding to the PTEN promoter (chromatin immunoprecipitation) and reduced both phosphorylated and oxidized (inactive) PTEN protein levels. Analysis of patient samples revealed 5-ASA that also reduced levels of active phosphorylated Akt in inflamed colitis tissue. Reduced PI3K/Akt signaling and expression of β-catenin target genes in 5-ASA–treated CUC patients additionally suggests enhanced PTEN activity as well.

Conclusions: Therefore, 5-ASA reduces CUC-induced reactive oxygen species in colonic progenitor cells and enhances PTEN activity, thus attenuating PI3K/Akt signaling. These data suggest that the antioxidant properties of 5-ASA may be the predominant mechanism for 5-ASA chemoprevention.

In Brief

Article first published online 17 July 2013

Author Information

Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Reprints: Terrence A. Barrett, MD, Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 N. St. Clair, Suite 1400, Chicago, IL 60611 (e-mail: tabarrett@northwestern.edu).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

The authors have no conflicts of interest to disclose.

Received March 15, 2013

Accepted April 18, 2013

© Crohn's & Colitis Foundation of America, Inc.

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