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

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*

Supplemental Author Material
Erratum

Erratum

In the article on page 514, volume 20, issue 3, the funding and conflict of interests statements were incomplete due to a production error.

The first sentence of the support footnote should read: “Supported by The Constance Travis Charitable Trust, Barts and The London Charity, Shire plc (Basingstoke, United Kingdom), the Dunhill Medical Trust, the Monument Trust, Bowel & Cancer Research and the NIH.”

The conflicts of interest footnote on the first page should read: “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, and has received honoraria for travel and speaking from AbbVie, and for speaking from MSD and Takeda. R. M. Feakins has received fees for expert testimony, for work with Unilabs-IHS, and received honoraria for speaking from the BDIAP, all for matters unrelated to this manuscript. R. Poulsom has received a consultancy fee from Genentech, Inc. The remaining authors have no conflicts of interest to disclose.”

Finally, the Acknowledgments’ penultimate sentence should read: The authors are also grateful for funding from Shire plc (Basingstoke, United Kingdom) under the Investigator-led Clinical Trials program, the Dunhill Medical Trust for funding from a Serendipity Award, the Monument Trust, and Bowel & Cancer Research and the NIH.”

Inflammatory Bowel Diseases. 20(4):775, April 2014.

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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 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.

Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

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