Increased sensitivity to dextran sodium sulfate colitis in IRE1 beta-deficient mice

The epithelial cells of the gastrointestinal tract are exposed to toxins an d infectious agents that can adversely affect protein folding in the endopl asmic reticulum (ER) and cause ER stress. The IRE1 genes are implicated in sensing and responding to ER stress signals. We found that epithelial cells of the gastrointestinal tract express IRE 1 beta, a specific isoform of IR E 1. BiP pro rein, a marker of ER stress, was elevated in the colonic mucos a of IRE1 beta (-/-) mice, and, when exposed to dextran sodium sulfate (DSS ) to induce inflammatory bowel disease, mutant mice developed colitis 3-5 d ays earlier than did wild-type or IRE1 beta (+/-) mice, The inflammation ma rker ICAM-1 was also expressed earlier in the colonic mucosa of DSS-treated IRE1 beta (-/-) mice, indicating that the mutation had its impact early in the inflammatory process, before the onset of mucosal ulceration. These fi ndings are consistent with a model whereby perturbations in ER function, wh ich are normally mitigated by the activity of IRE1 beta, participate in the development of colitis.