Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients. (3rd November 2018)

• Record Type: Journal Article
• Authors: Kawamoto, Ami; Nagata, Sayaka; Anzai, Sho; Takahashi, Junichi; Kawai, Mao; Hama, Minami; Nogawa, Daichi; Yamamoto, Kouhei; Kuno, Reiko; Suzuki, Kohei; Shimizu, Hiromichi; Hiraguri, Yui; Yui, Shiro; Oshima, Shigeru; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Ohtsuka, Kazuo; Kitagawa, Masanobu; Okamoto, Ryuichi; Watanabe, Mamoru
• Is Part Of: Journal of Crohn's and colitis. Volume 13:Number 4(2019)
• Page Start: 495
• Page End: 509
• Publication Date: 2018-11-03
• Subjects: Tumour necrosis factor alpha [TNF-α] -- Notch pathway -- ubiquitin D [UBD]; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjy180
• Languages: English
• ISSNs: 1873-9946

Abstract

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.