title: Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam, 3015 CE Rotterdam, The Netherlands. j.deuring@erasmusmc.nl
authors.forename: J Jasper
authors.initials: JJ
authors.lastname: Deuring
authors.forename: Colin
authors.initials: C
authors.lastname: de Haar
authors.forename: Chantal L
authors.initials: CL
authors.lastname: Koelewijn
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: C Janneke
authors.initials: CJ
authors.lastname: van der Woude
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000145:classification / Q000378:metabolism*; D003424:Crohn Disease / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins