title: Altered endoplasmic reticulum stress affects translation in inactive colon tissue from patients with ulcerative colitis.
abstract: OBJECTIVE
  Ulcerative colitis (UC) is a chronic inflammatory disorder that affects the colonic epithelium. Epidemiology studies indicate an environmental component is involved in pathogenesis, although the primary changes in the digestive epithelium that cause an uncontrolled inflammatory response are not known. Animal studies have shown that altered endoplasmic reticulum (ER) stress response initiates intestinal inflammation in epithelial tissues, but abnormalities associated with ER stress have not been identified in patients with UC.
  
  
  METHODS
  Using immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence analyses, we assessed ER stress signaling in uninflammed colonic mucosa from patients with UC and controls. Genome-wide microarray analysis of actively translated polysome-bound messenger RNA was performed using samples of unaffected mucosa from patients with UC, and data were compared with those from controls.
  
  
  RESULTS
  Inositol-requiring kinase and activating transcription factor signaling pathways were activated in inactive colonic epithelium from patients with UC; these mediate proinflammatory and regenerative responses. Blocking phosphorylation of the translation initiation factor 2 (eIF2α), which mediates the integrated stress response, deregulated initiation of translation and reduced the numbers of stress granules in colonic epithelial cells from patients with UC. Genome-wide microarray analysis of actively translated, polysome-bound messenger RNA from patients revealed changes in protein translation that altered colonic epithelial barrier function (levels of detoxification and antioxidant enzymes and proteins that regulate the cell cycle, cell-cell adhesion, and secretion), compared with controls.
  
  
  CONCLUSIONS
  Colonic mucosa samples from patients with UC have defects in the eIF2α pathway that controls protein translation and the cell stress response. This pathway might be investigated to identify new therapeutic targets for patients with UC.
authors.affiliation: INSERM, U773, Centre de Recherche Bichat-Beaujon CRB3, Paris, France. xavier.treton@bjn.aphp.fr
authors.forename: Xavier
authors.initials: X
authors.lastname: Tréton
authors.forename: Eric
authors.initials: E
authors.lastname: Pédruzzi
authors.forename: Dominique
authors.initials: D
authors.lastname: Cazals-Hatem
authors.forename: Alain
authors.initials: A
authors.lastname: Grodet
authors.forename: Yves
authors.initials: Y
authors.lastname: Panis
authors.forename: André
authors.initials: A
authors.lastname: Groyer
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
authors.forename: Yoram
authors.initials: Y
authors.lastname: Bouhnik
authors.forename: Fanny
authors.initials: F
authors.lastname: Daniel
authors.forename: Eric
authors.initials: E
authors.lastname: Ogier-Denis
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D001706:Biopsy; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015536:Down-Regulation / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism; D046228:Microarray Analysis; D014176:Protein Biosynthesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D012333:RNA, Messenger; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases