Ubiquitin D is up-regulated by synergy of Notch signaling and TNF-α in the inflamed intestinal epithelia of IBD patients.

Ubiquitin D is up-regulated by synergy of Notch signaling and TNF-α in the inflamed intestinal epithelia of IBD patients.

Abstract

Background and Aims: The intestinal epithelium of inflammatory bowel disease (IBD) patients is exposed to various pro-inflammatory cytokines, most notably TNF-α. We have previously shown that the Notch signalling pathway is also up-regulated 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: 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: 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 up-regulated 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) down-regulation of UBD reflected favourable outcome in IBD patients. Conclusion: We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-α treatment.

Journal Article

JOUNAL:
Journal of Crohn’s and Colitis

TITLE:
Ubiquitin D is up-regulated by synergy of Notch signaling and TNF-α in the inflamed intestinal epithelia of IBD patients.

DOI:
https://doi.org/10.1093/ecco-jcc/jjy180

Correspondence to

Ryuichi Okamoto, Professor
Department of Gastroenterology and Hepatology
Graduate School of Medical and Dental Sciences
Tokyo Medical and Dental University (TMDU)
E-mail: rokamoto.gast(at)tmd.ac.jp