DUOX2 and DUOXA2 form the predominant enzyme system capable of producing the reactive oxygen species H2O2 in active ulcerative colitis and are modulated by 5-aminosalicylic acid

Tammie S. MacFie, Richard Poulsom, Alexandra Parker, Gary Warnes, Tatjana Boitsova, Anke Nijhuis, Nirosha Suraweera, Angela Poehlmann, Jaroslaw Szary, Roger Feakins, Rosemary Jeffery, Richart W Harper, Adrian M. Jubb, James O. Lindsay, Andrew Silver

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Abstract

Background: NADPH oxidase-derived reactive oxygen species, such as H2O2, are part of the intestinal innate immune system but may drive carcinogenesis through DNA damage. We sought to identify the predominant enzyme system capable of producing H2O2 in active ulcerative colitis and assess whether it is affected by 5-aminosalicylic acid (5-ASA). Methods: We studied human mucosal biopsies by expression arrays, quantitative real-time polymerase chain reaction for NADPH oxidase family members, in situ hybridization (DUOX2 and DUOXA2) and immunofluorescence for DUOX, 8-OHdG (DNA damage), and gH2AX (DNA damage response) and sought effects of 5-ASA on ex vivo cultured biopsies and cultured rectal cancer cells. Results: DUOX2 with maturation partner DUOXA2 forms the predominant system for H2O2 production in human colon and is upregulated in active colitis. DUOX2 in situ is exclusively epithelial, varies between and within individual crypts, and increases near inflammation. 8-OHdG and gH2AX were observed in damaged crypt epithelium. 5-ASA upregulated DUOX2 and DUOXA2 levels in the setting of active versus quiescent disease and altered DUOX2 expression in cultured biopsies. Ingenuity pathway analysis confirmed that inflammation status and 5-ASA increase expression of DUOX2 and DUOXA2. An epithelial cell model confirmed that cultured cancer cells expressed DUOX protein and produced H2O2 in response to hypoxia and 5-SA exposure. Conclusions: Both DUOX2 and DUOXA2 expression are involved specifically in inflammation and are regulated on a crypt-by-crypt basis in ulcerative colitis tissues. Synergy between inflammation, hypoxia, and 5-ASA to increase H2O2 production could explain how 5-ASA supports innate defense, although potentially increasing the burden of DNA damage.

Original languageEnglish (US)
Pages (from-to)514-524
Number of pages11
JournalInflammatory Bowel Diseases
Volume20
Issue number3
DOIs
StatePublished - 2014

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Keywords

  • DNA damage
  • Hydrogen peroxide
  • Mesalazine
  • Ulcerative colitis

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

MacFie, T. S., Poulsom, R., Parker, A., Warnes, G., Boitsova, T., Nijhuis, A., Suraweera, N., Poehlmann, A., Szary, J., Feakins, R., Jeffery, R., Harper, R. W., Jubb, A. M., Lindsay, J. O., & Silver, A. (2014). DUOX2 and DUOXA2 form the predominant enzyme system capable of producing the reactive oxygen species H2O2 in active ulcerative colitis and are modulated by 5-aminosalicylic acid. Inflammatory Bowel Diseases, 20(3), 514-524. https://doi.org/10.1097/01.MIB.0000442012.45038.0e