RRC ID 54388
Author Kawamoto A, Nagata S, Anzai S, Takahashi J, Kawai M, Hama M, Nogawa D, Yamamoto K, Kuno R, Suzuki K, Shimizu H, Hiraguri Y, Yui S, Oshima S, Tsuchiya K, Nakamura T, Ohtsuka K, Kitagawa M, Okamoto R, Watanabe M.
Title Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients.
Journal J Crohns Colitis
Abstract BACKGROUND AND AIMS: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: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 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:We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-α treatment.
Volume 13(4)
Pages 495-509
Published 2019-3-30
DOI 10.1093/ecco-jcc/jjy180
PII 5160030
PMID 30395194
MeSH Anti-Bacterial Agents / pharmacology Cell Line Doxycycline / pharmacology Drug Synergism Epithelial Cells / metabolism Gastrointestinal Agents / pharmacology Gastrointestinal Agents / therapeutic use Gene Expression Gene Expression Regulation Humans Inflammatory Bowel Diseases / drug therapy Inflammatory Bowel Diseases / genetics* Inflammatory Bowel Diseases / metabolism* Inflammatory Bowel Diseases / pathology Infliximab / pharmacology Infliximab / therapeutic use Intestinal Mucosa / metabolism NF-kappa B / metabolism Organoids / metabolism Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction Transcription, Genetic Transcriptome Tumor Necrosis Factor-alpha / metabolism* Tumor Necrosis Factor-alpha / pharmacology Ubiquitins / genetics* Ubiquitins / metabolism* Up-Regulation
IF 7.827
Times Cited 2
DNA material pGa981-6 (RDB06776)