C/EBP homologous protein inhibits tissue repair in response to gut injury and is inversely regulated with chronic inflammation.
Loss of intestinal epithelial cell (IEC) homeostasis and apoptosis negatively affect intestinal barrier function. Uncontrolled activation of the unfolded protein response (UPR) in IEC contributes to an impaired barrier and is implicated in the pathogenesis of inflammatory bowel diseases. However, the contribution of the UPR target gene C/EBP homologous protein (CHOP), an apoptosis-associated transcription factor, to inflammation-related disease susceptibility remains unclear. Consistent with observations in patients with ulcerative colitis, we show that despite UPR activation in the epithelium, CHOP expression was reduced in mouse models of T-cell-mediated and bacteria-driven colitis. To elucidate the molecular mechanisms of IEC-specific CHOP expression, we generated a conditional transgenic mouse model (Chop(IEC Tg/Tg)). Chop overexpression increased the susceptibility toward dextran sodium sulfate (DSS)-induced intestinal inflammation and mucosal tissue injury. Furthermore, a delayed recovery from DSS-induced colitis and impaired closure of mechanically induced mucosal wounds was observed. Interestingly, these findings seemed to be independent of CHOP-mediated apoptosis. In vitro and in vivo cell cycle analyses rather indicated a role for CHOP in epithelial cell proliferation. In conclusion, these data show that IEC-specific overexpression impairs epithelial cell proliferation and mucosal tissue regeneration, suggesting an important role for CHOP beyond mediating apoptosis.
1] Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany [2] ZIEL-Research Center for Nutrition and Food Sciences, Biofunctionality Unit, Technische Universität München, Freising, Germany.
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Waldschmitt
Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany.
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Berger
Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany.
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Rath
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
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Sartor
First Medical Clinic, University of Erlangen, Erlangen, Germany.
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Weigmann
Institute of Virology, Technische Universität München/Helmholtz Zentrum Munich, Munich, Germany.
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Heikenwalder
Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
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Gerhard
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
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Janssen
1] Chair of Nutrition and Immunology, Technische Universität München, Freising, Germany [2] ZIEL-Research Center for Nutrition and Food Sciences, Biofunctionality Unit, Technische Universität München, Freising, Germany.
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Haller
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D012038:Regeneration / Q000235:genetics / Q000276:immunology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000276:immunology*; D056811:Unfolded Protein Response / Q000235:genetics / Q000276:immunology
C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP