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.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Colitis/metabolism , Crohn Disease/metabolism , Gene Expression Regulation/physiology , Intestinal Mucosa/metabolism , Neoplasm Proteins/metabolism , Protein Folding , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Colitis/classification , Endoplasmic Reticulum Chaperone BiP , Epithelial Cells/metabolism , HEK293 Cells , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Humans , Inflammation/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/pathology , Neoplasm Proteins/geneticsABSTRACT
AIM: To explore if C-reactive protein (CRP) levels might serve as a prognostic factor with respect to the clinical course of Crohn's disease and might be useful for classification. METHODS: In this retrospective cohort study we enrolled 94 patients from the inflammatory bowel disease (IBD) database of the University Medical Centre Utrecht. CRP levels during relapse were correlated with the number of relapses per year. Severity of relapses was based on endoscopic reports and prednisone use. Furthermore, patients were categorized in a low or high CRP group based on their CRP response during relapse and demographic and clinical features were compared. RESULTS: Overall, a positive correlation between CRP levels, number of relapses, and severity of relapse was found (respectively rs = 0.31, P < 0.01 and rs = 0.50, P < 0.001). Employing a cut-off level of 15 mg/L, the index CRP level was found to discriminate patients with respect to the number of relapses per year, as well as for severity of relapses (respectively 0.25 +/- 0.16 vs 0.36 +/- 0.24, P < 0.05 and 4.4 +/- 1.2 vs 3.2 +/- 1.1 on a 10-point visual analogue scale, P < 0.001 for the high CRP and low CRP groups respectively). In addition, the high CRP group showed more cumulative days of prednisone use per year (107 +/- 95 vs 58 +/- 48, P < 0.05), as well as a better response to infliximab (93 % vs 33 %, P = 0.06). CONCLUSION: A higher CRP level during relapse seems to be associated with a more severe clinical course of disease.
