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http://purl.uniprot.org/citations/30395194http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30395194http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.org/dc/terms/identifier"doi:10.1093/ecco-jcc/jjy180"xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Kitagawa M."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Nakamura T."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Suzuki K."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Tsuchiya K."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Shimizu H."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Watanabe M."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Yamamoto K."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Oshima S."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Takahashi J."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Kawai M."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Nagata S."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Okamoto R."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Ohtsuka K."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Yui S."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Kawamoto A."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Hama M."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Kuno R."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Anzai S."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Hiraguri Y."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/author"Nogawa D."xsd:string
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/date"2019"xsd:gYear
http://purl.uniprot.org/citations/30395194http://purl.uniprot.org/core/name"J Crohns Colitis"xsd:string
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