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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

MacFie, Tammie S. PhD*; Poulsom, Richard DSc*,†; Parker, Alexandra PhD*; Warnes, Gary PhD; Boitsova, Tatjana BSc*; Nijhuis, Anke MSc*; Suraweera, Nirosha PhD*; Poehlmann, Angela PhD§; Szary, Jaroslaw PhD*; Feakins, Roger MB, BCh, BAO; Jeffery, Rosemary*,†; Harper, Richart W. PhD; Jubb, Adrian M. PhD**; Lindsay, James O. PhD*; Silver, Andrew PhD*

doi: 10.1097/01.MIB.0000442012.45038.0e
Original Clinical Articles

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 γH2AX (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 γH2AX 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-ASA 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.

Article first published online 31 January 2014

*Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, United Kingdom;

National Centre for Bowel Research and Surgical Innovation, Barts and The London School of Medicine and Dentistry, Whitechapel, London, United Kingdom;

Flow Cytometry Core Facility, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, United Kingdom;

§Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany;

Department of Cellular Pathology, Royal London Hospital, London, United Kingdom;

Division of Pulmonary and Critical Care Medicine, Genome and Biomedical Sciences Facility, University of California at Davis, Davis, California; and

**Department of Pathology, Genentech, Inc., South San Francisco, California.

Reprints: Andrew Silver, PhD or James Lindsay, PhD, Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, Whitechapel, London E1 2AT, United Kingdom (e-mail: a.r.silver@qmul.ac.uk or james.lindsay@bartshealth.nhs.uk).

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).

Supported by The Constance Travis Charitable Trust, Barts and The London Charity, Shire plc (Basingstoke, United Kingdom), the Dunhill Medical Trust, the Monument Trust, and Bowel & Cancer Research. The study sponsors had no role in study design; in the collection, analysis and interpretation data; in the writing of the report; or in the decision to submit the paper for publication.

Presented in part as poster presentations accompanied by meeting abstracts (PO 414, 19th United European Gastroenterology Week, Stockholm, October 22–26, 2011; PWE-255, Digestive Disorders Federation, Liverpool, June 17–20, 2012).

A. M. Jubb is an employee of Genentech, Inc., and holds equity in Roche. J. O. Lindsay sits on the advisory board of, and has received honoraria for speaking from, Shire UK, Warner Chilcott UK, and Ferring. R. Poulsom has received a consultancy fee from Genentech, Inc. The remaining authors have no conflicts of interest to disclose.

Received October 28, 2013

Accepted December 16, 2013

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