Xenotoxic damage in inflammatory diseases, including IBD (inflammatory bowel disease), is compounded by reduced activity of the xenobiotic transporter ABCG2 (ATP-binding-cassette G2) during the inflammatory state. An association between the activation of the unfolded protein response pathway and inflammation prompted us to investigate the possibility that reduced ABCG2 activity is causally linked to this response. To this end, we correlated expression of ABCG2 and the unfolded protein response marker GRP78 (glucose-regulated protein of 78 kDa) in colon biopsies from healthy individuals (n=9) and patients with inactive (n=67) or active (n=55) IBD, ischaemic colitis (n=10) or infectious colitis (n=14). In addition, tissue specimens throughout the small bowel from healthy individuals (n=27) and from patients with inactive (n=9) or active (n=25) Crohn's disease were co-stained for ABCG2 and GRP78. In all biopsies from patients with active inflammation, irrespective of the underlying disease, an absolute negative correlation was observed between epithelial ABCG2 expression and GRP78 expression, suggesting that inflammation-dependent activation of the unfolded protein response is responsible for suppression of ABCG2 function. The link between the unfolded protein response and functional ABCG2 expression was further corroborated by live imaging of ABCG2-expressing cells, which showed that various inflammatory mediators, including nitric oxide, activate the unfolded protein response and concomitantly reduce plasma membrane localization as well as transport function of ABCG2. Thus a novel mechanism for explaining xenobiotic stress during inflammation emerges in which intestinal inflammation activates the unfolded protein response, in turn abrogating defences against xenobiotic challenge by impairing ABCG2 expression and function.
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Research Article|
December 14 2011
Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding Available to Purchase
J. Jasper Deuring;
J. Jasper Deuring
1
1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, 3015 CE Rotterdam, The Netherlands
1To whom correspondence should be addressed (email [email protected]).
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Colin de Haar;
Colin de Haar
1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, 3015 CE Rotterdam, The Netherlands
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Chantal L. Koelewijn;
Chantal L. Koelewijn
1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, 3015 CE Rotterdam, The Netherlands
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Ernst J. Kuipers;
Ernst J. Kuipers
1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, 3015 CE Rotterdam, The Netherlands
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Maikel P. Peppelenbosch;
Maikel P. Peppelenbosch
1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, 3015 CE Rotterdam, The Netherlands
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C. Janneke van der Woude
C. Janneke van der Woude
1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, 3015 CE Rotterdam, The Netherlands
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Publisher: Portland Press Ltd
Received:
July 18 2011
Revision Received:
August 19 2011
Accepted:
August 25 2011
Accepted Manuscript online:
August 25 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (1): 87–93.
Article history
Received:
July 18 2011
Revision Received:
August 19 2011
Accepted:
August 25 2011
Accepted Manuscript online:
August 25 2011
Citation
J. Jasper Deuring, Colin de Haar, Chantal L. Koelewijn, Ernst J. Kuipers, Maikel P. Peppelenbosch, C. Janneke van der Woude; Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding. Biochem J 1 January 2012; 441 (1): 87–93. doi: https://doi.org/10.1042/BJ20111281
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