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Waldschmitt, N.* ; Berger, E.* ; Rath, E.* ; Sartor, R.B.* ; Weigmann, B.* ; Heikenwälder, M. ; Gerhard, M.* ; Janssen, K.P.* ; Haller, D.*

C/EBP homologous protein inhibits tissue repair in response to gut injury and is inversely regulated with chronic inflammation.

Mucosal Immunol. 7, 1452-1466 (2014)
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Endoplasmic-reticulum Stress; Intestinal Epithelial-cells; Bowel-disease; Er Stress; Ulcerative-colitis; Chop Gadd153; Transcription Factors; Crohns-disease; Apoptosis; Mice
ISSN (print) / ISBN 1933-0219
e-ISSN 1933-0219
Zeitschrift Mucosal Immunology
Quellenangaben Band: 7, Heft: 6, Seiten: 1452-1466 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort UNITED STATES
Begutachtungsstatus Peer reviewed