XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease

Cell. 2008 Sep 5;134(5):743-56. doi: 10.1016/j.cell.2008.07.021.


Inflammatory bowel disease (IBD) has been attributed to aberrant mucosal immunity to the intestinal microbiota. The transcription factor XBP1, a key component of the endoplasmic reticulum (ER) stress response, is required for development and maintenance of secretory cells and linked to JNK activation. We hypothesized that a stressful environmental milieu in a rapidly proliferating tissue might instigate a proinflammatory response. We report that Xbp1 deletion in intestinal epithelial cells (IECs) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell dysfunction and an epithelium that is overly reactive to inducers of IBD such as bacterial products (flagellin) and TNFalpha. An association of XBP1 variants with both forms of human IBD (Crohn's disease and ulcerative colitis) was identified and replicated (rs35873774; p value 1.6 x 10(-5)) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IECs, thus linking cell-specific ER stress to the induction of organ-specific inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Colitis, Ulcerative / genetics
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / pathology
  • Crohn Disease / genetics
  • Crohn Disease / immunology
  • Crohn Disease / pathology
  • DNA-Binding Proteins / immunology*
  • Endoplasmic Reticulum / immunology*
  • Genetic Predisposition to Disease
  • Humans
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / pathology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Listeria monocytogenes / immunology
  • Mice
  • Mice, Transgenic
  • Paneth Cells / cytology
  • Paneth Cells / metabolism
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / immunology*
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse