Concerning colonic Niraparib samples , a significantly increased concentration of HSPA5 was CPI-613 structure observed in inflamed samples of UC patients when compared to healthy controls . Furthermore, a significant increase in PDIA4 concentration was observed in inflamed samples of both UC and CD patients, which could reflect the activation of ATF6 . The activation of IRE1 was assessed by the presence of the prototypical XBP1s, but no significant differential expression was observed in colonic inflamed samples of IBD patients . Activation of the PERK branch results in the phosphorylation of EIF2A, and significant increase in levels of pEIF2A/EIF2A was demonstrated in inflamed colonic IBD samples . No significant differential expression of GADD34 protein was observed . Concerning ileal samples , concentrations of HSPA5, PDIA4, XBP1s, GADD34 and pEIF2A in ileal control samples were comparable to those observed in inflamed samples of ileal CD patients . Interestingly, protein levels correlated generally with our mRNA data and when not significant, a similar trend was observed. The basal activation of the UPR in the healthy ileal tissue questions the capacity of the ileum to establish any further ER stress response, a fact that could artificially mask the increase due to a pathologic situation. To test whether the ileal tissue is still responsive to ER stress stimuli, we stimulated paired colonic and ileal mucosal samples of five healthy controls with tunicamycin. Tunicamycin blocks protein glycosylation and consequently induces the UPR. Transcriptional analysis of HSPA5 revealed an increased expression in both tunicamycin stimulated colonic and ileal mucosal samples when compared to unstimulated samples . In addition, a more pronounced induction was observed in ileal samples when compared to colonic samples . This shows that although the ileum lives with a higher basal UPR engagement , it remains responsive to further ER stress induction. An elevation of ER stress in the whole tissue could reflect either an increase of ER stress in the local tissue, or a more marked ER stress in inflammatory cells recruited to the site of inflammation. To delineate which of these possibilities is involved in our results, we performed immunohistochemistry using HSPA5, a central chaperone induced upon ER stress. HSPA5 was mainly localized to the epithelial lining of the gut and in Paneth cells, positive signal also comes from inflammatory cells .