Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients.
Anti-Bacterial Agents
/ pharmacology
Cell Line
Doxycycline
/ pharmacology
Drug Synergism
Epithelial Cells
/ metabolism
Gastrointestinal Agents
/ pharmacology
Gene Expression
Gene Expression Regulation
Humans
Inflammatory Bowel Diseases
/ drug therapy
Infliximab
/ pharmacology
Intestinal Mucosa
/ metabolism
NF-kappa B
/ metabolism
Organoids
/ metabolism
Receptors, Notch
/ genetics
Signal Transduction
Transcription, Genetic
Transcriptome
Tumor Necrosis Factor-alpha
/ metabolism
Ubiquitins
/ genetics
Up-Regulation
Notch pathway
Tumour necrosis factor alpha [TNF-α]
ubiquitin D [UBD]
Journal
Journal of Crohn's & colitis
ISSN: 1876-4479
Titre abrégé: J Crohns Colitis
Pays: England
ID NLM: 101318676
Informations de publication
Date de publication:
30 Mar 2019
30 Mar 2019
Historique:
pubmed:
6
11
2018
medline:
6
8
2019
entrez:
6
11
2018
Statut:
ppublish
Résumé
The intestinal epithelium of inflammatory bowel disease [IBD] patients is exposed to various pro-inflammatory cytokines, most notably tumour necrosis factor alpha [TNF-α]. We have previously shown that the Notch signalling pathway is also upregulated in such an epithelium, contributing to intestinal epithelial cell [IEC] proliferation and regeneration. We aimed to reproduce such environment in vitro and explore the gene regulation involved. Human IEC cell lines or patient-derived organoids were used to analyse Notch- and TNF-α-dependent gene expression. Immunohistochemistry was performed to analyse expression of ubiquitin D [UBD] in various patient-derived intestinal tissues. In human IEC cell lines, we found that Notch signalling and TNF-α-induced NFκB signalling are reciprocally regulated to promote expression of a specific gene subset. Global gene expression analysis identified UBD to be one of the most highly upregulated genes, due to synergy of Notch and TNF-α. The synergistic expression of UBD was regulated at the transcriptional level, whereas the UBD protein had an extremely short half-life due to post-translational, proteasomal degradation. In uninflamed intestinal tissues from IBD patients, UBD expression was limited to IECs residing at the crypt bottom. In contrast, UBD-expressing IECs were seen throughout the crypt in inflamed tissues, indicating substantial induction by the local inflammatory environment. Analysis using patient-derived organoids consistently confirmed conserved Notch- and TNF-α-dependent expression of UBD. Notably, post-infliximab [IFX] downregulation of UBD reflected favourable outcome in IBD patients. We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-α treatment.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
The intestinal epithelium of inflammatory bowel disease [IBD] patients is exposed to various pro-inflammatory cytokines, most notably tumour necrosis factor alpha [TNF-α]. We have previously shown that the Notch signalling pathway is also upregulated in such an epithelium, contributing to intestinal epithelial cell [IEC] proliferation and regeneration. We aimed to reproduce such environment in vitro and explore the gene regulation involved.
METHODS
METHODS
Human IEC cell lines or patient-derived organoids were used to analyse Notch- and TNF-α-dependent gene expression. Immunohistochemistry was performed to analyse expression of ubiquitin D [UBD] in various patient-derived intestinal tissues.
RESULTS
RESULTS
In human IEC cell lines, we found that Notch signalling and TNF-α-induced NFκB signalling are reciprocally regulated to promote expression of a specific gene subset. Global gene expression analysis identified UBD to be one of the most highly upregulated genes, due to synergy of Notch and TNF-α. The synergistic expression of UBD was regulated at the transcriptional level, whereas the UBD protein had an extremely short half-life due to post-translational, proteasomal degradation. In uninflamed intestinal tissues from IBD patients, UBD expression was limited to IECs residing at the crypt bottom. In contrast, UBD-expressing IECs were seen throughout the crypt in inflamed tissues, indicating substantial induction by the local inflammatory environment. Analysis using patient-derived organoids consistently confirmed conserved Notch- and TNF-α-dependent expression of UBD. Notably, post-infliximab [IFX] downregulation of UBD reflected favourable outcome in IBD patients.
CONCLUSION
CONCLUSIONS
We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-α treatment.
Identifiants
pubmed: 30395194
pii: 5160030
doi: 10.1093/ecco-jcc/jjy180
doi:
Substances chimiques
Anti-Bacterial Agents
0
Gastrointestinal Agents
0
NF-kappa B
0
Receptors, Notch
0
Tumor Necrosis Factor-alpha
0
UBD protein, human
0
Ubiquitins
0
Infliximab
B72HH48FLU
Doxycycline
N12000U13O
Types de publication
Journal Article
Langues
eng
Pagination
495-509Informations de copyright
Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.