Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding

未折叠蛋白反应 炎症 炎症性肠病 Abcg2型 免疫学 结肠炎 氧化应激 化学 生物 医学 运输机 内科学 ATP结合盒运输机 疾病 生物化学 内质网 基因
作者
J. Jasper Deuring,Colin de Haar,Chantal L Koelewijn,Ernst J. Kuipers,Maikel P. Peppelenbosch,Jean–Frédéric Colombel
出处
期刊:Biochemical Journal [Portland Press]
卷期号:441 (1): 87-93 被引量:38
标识
DOI:10.1042/bj20111281
摘要

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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