title: The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress has been associated with development of inflammatory bowel disease. We examined the effects of ER stress-induced chaperone response and the orally active chemical chaperones tauroursodeoxycholate (TUDCA) and 4-phenylbutyrate (PBA), which facilitate protein folding and reduce ER stress, in mice with colitis.
  
  
  METHODS
  We used dextran sulfate sodium (DSS) to induce colitis in mice that do not express the transcription factor ATF6α or the protein chaperone P58(IPK). We examined the effects of TUDCA and PBA in cultured intestinal epithelial cells (IECs); in wild-type, P58(IPK-/-), and Atf6α(-/-) mice with colitis; and in Il10(-/-) mice.
  
  
  RESULTS
  P58(IPK-/-) and Atf6α(-/-) mice developed more severe colitis following administration of DSS than wild-type mice. IECs from P58(IPK-/-) mice had excessive ER stress, and apoptotic signaling was activated in IECs from Atf6α(-/-) mice. Inflammatory stimuli induced ER stress signals in cultured IECs, which were reduced by incubation with TUDCA or PBA. Oral administration of either PBA or TUDCA reduced features of DSS-induced acute and chronic colitis in wild-type mice, the colitis that develops in Il10(-/-) mice, and DSS-induced colitis in P58(IPK-/-) and Atf6α(-/-) mice. Reduced signs of colonic inflammation in these mice were associated with significantly decreased ER stress in colonic epithelial cells.
  
  
  CONCLUSIONS
  The unfolded protein response induces expression of genes that encode chaperones involved in ER protein folding; these factors prevent induction of colitis in mice. Chemical chaperones such as TUDCA and PBA alleviate different forms of colitis in mice and might be developed for treatment of inflammatory bowel diseases.
authors: Del E. Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Stewart Siyan
authors: SS
authors: Cao
authors: Ellen M
authors: EM
authors: Zimmermann
authors: Brandy-Mengchieh
authors: BM
authors: Chuang
authors: Benbo
authors: B
authors: Song
authors: Anosike
authors: A
authors: Nwokoye
authors: J Erby
authors: JE
authors: Wilkinson
authors: Kathryn A
authors: KA
authors: Eaton
authors: Randal J
authors: RJ
authors: Kaufman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D015398:Signal Transduction / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D018832:Molecular Chaperones; D004247:DNA