Endoplasmic reticulum stress and unfolded protein response in inflammatory bowel disease

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45 Scopus citations


In eukaryotic cells, protein folding and modification in the endoplasmic reticulum (ER) is highly sensitive to disturbances of homeostasis. The accumulation of unfolded and misfolded proteins in the ER lumen, termed ER stress, activates intracellular signaling pathways to resolve the protein-folding defect. This unfolded protein response (UPR) increases the capacity of ER protein folding, reduces global protein synthesis, and activates ER-associated protein degradation. If ER stress is too severe or chronic, or the UPR is compromised and not able to restore ER protein-folding homeostasis, numerous apoptotic signaling pathways are activated. Preclinical and clinical studies in the past decade indicate that ER stress and the UPR have a significant impact on the pathogenesis of inflammatory bowel disease. Paneth and goblet cells, 2 epithelial cell populations in the gut, rely on a robust ER function for protein folding and secretion. Several immune cells are orchestrated by ER stress and the UPR for differentiation, activation, migration, and survival. In addition, a variety of exogenous and endogenous molecules in the intestinal lumen affect ER function, making ER stress and the UPR relevant cellular signals in intestinal homeostasis. Recent studies demonstrated that unresolved ER stress and/or dysregulated UPR may cause inflammatory bowel disease by inducing epithelial cell death, impairing mucosal barrier function, and activating proinflammatory response in the gut. With our increased understanding of ER stress in inflammatory bowel disease pathogenesis, it is now possible to develop novel therapies to improve ER protein-folding homeostasis and target-specific UPR pathways in cells residing in the intestinal mucosa.

Original languageEnglish
Pages (from-to)636-644
Number of pages9
JournalInflammatory bowel diseases
Issue number3
StatePublished - Jan 9 2015


  • apoptosis
  • intestinal epithelial cells
  • mucosal immunity
  • new therapies
  • protein folding and secretion


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