Abstract
BackgroundEndoplasmic reticulum (ER) stress has been suggested to play a role in inflammatory bowel disease (IBD). The three branches (ATF6, IRE1 and PERK) of the unfolded protein response (UPR) have different roles and are not necessarily activated simultaneously.Methodology/Principal FindingsExpression of UPR-related genes was investigated in colonic and ileal biopsies of 23 controls, 15 ulcerative colitis (UC) and 54 Crohn's disease (CD) patients. This expression was confirmed at protein level in colonic and ileal samples of five controls, UC and CD patients. HSPA5, PDIA4 and XBP1s were significantly increased in colonic IBD at mRNA and/or protein levels, indicating activation of the ATF6 and IRE1 branch. Colonic IBD was associated with increased phosphorylation of EIF2A suggesting the activation of the PERK branch, but subsequent induction of GADD34 was not observed. In ileal CD, no differential expression of the UPR-related genes was observed, but our data suggested a higher basal activation of the UPR in the ileal mucosa of controls. This was confirmed by the increased expression of 16 UPR-related genes as 12 of them were significantly more expressed in ileal controls compared to colonic controls. Tunicamycin stimulation of colonic and ileal samples of healthy individuals revealed that although the ileal mucosa is exhibiting this higher basal UPR activation, it is still responsive to ER stress, even more than colonic mucosa.Conclusions/SignificanceActivation of the three UPR-related arms is seen in colonic IBD-associated inflammation. However, despite EIF2A activation, inflamed colonic tissue did not increase GADD34 expression, which is usually involved in re-establishment of ER homeostasis. This study also implies the presence of a constitutive UPR activation in healthy ileal mucosa, with no further activation during inflammation. Therefore, engagement of the UPR differs between colon and ileum and this could be a factor in the development of ileal or colonic disease.
Highlights
Inflammatory bowel disease (IBD) is a group of chronic, inflammatory disorders of the colon and/or small intestine
An extensive set of colonic (Fig. 1A) and ileal samples (Fig. 1B) of healthy controls, ulcerative colitis (UC) and Crohn’s disease (CD) patients was evaluated for IL8 mRNA to confirm and define inflammation in endoscopic pinch biopsies
Endoplasmic reticulum (ER) stress is a common feature of intestinal secretory cells such as Paneth cells, enteroendocrine cells and to a lesser extent goblet cells
Summary
Inflammatory bowel disease (IBD) is a group of chronic, inflammatory disorders of the colon and/or small intestine. The precise pathophysiology of the diseases remains incompletely understood, recent studies link endoplasmic reticulum (ER) stress to these inflammatory conditions. A variety of stimuli, including virus infections, and endogenous imbalances in the cell, such as the accumulation of unfolded or misfolded proteins, the loss of calcium homeostasis, glucose deprivation, or the accumulation of free cholesterol can increase stress to the ER [2,3]. To cope with stressful conditions and to ensure correct protein folding, eukaryotic cells have evolved the unfolded protein response (UPR) which restores normal cell function by cessation of protein translation, increase of chaperones production and degradation of aberrant proteins [4,5]. Endoplasmic reticulum (ER) stress has been suggested to play a role in inflammatory bowel disease (IBD). The three branches (ATF6, IRE1 and PERK) of the unfolded protein response (UPR) have different roles and are not necessarily activated simultaneously
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