Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients

• Main Authors: Reiko Kuno, Go Ito, Ami Kawamoto, Yui Hiraguri, Hady Yuki Sugihara, Sayaka Takeoka, Sayaka Nagata, Junichi Takahashi, Mao Tsuchiya, Sho Anzai, Tomohiro Mizutani, Hiromichi Shimizu, Shiro Yui, Shigeru Oshima, Kiichiro Tsuchiya, Mamoru Watanabe, Ryuichi Okamoto
• Format: Article
• Language: English
• Published: Elsevier 2021-03-01
• Series: Biochemistry and Biophysics Reports
• Subjects: Tumour necrosis factor-α (TNF-α); Notch pathway; OLFM4
• Online Access: http://www.sciencedirect.com/science/article/pii/S2405580820302168

Notch signaling is activated in the intestinal epithelial cells (IECs) of patients with inflammatory bowel disease (IBD), and contributes to mucosal regeneration. Our previous study indicated that TNF-α and Notch signaling may synergistically promote the expression of the intestinal stem cell (ISC) marker OLFM4 in human IECs. In the present study, we investigated the gene regulation and function of OLFM4 in human IEC lines. We confirmed that TNF-α and Notch synergistically upregulate the mRNA expression of OLFM4. Luciferase reporter assay showed that OLFM4 transcription is regulated by the synergy of TNF-α and Notch. At the protein level, synergy between TNF-α and Notch promoted cytoplasmic accumulation of OLFM4, which has potential anti-apoptotic properties in human IECs. Analysis of patient-derived tissues and organoids consistently showed cytoplasmic accumulation of OLFM4 in response to NF-κB and Notch activation. Cytoplasmic accumulation of OLFM4 in human IECs is tightly regulated by Notch and TNF-α in synergy. Such cytoplasmic accumulation of OLFM4 may have a cell-protective role in the inflamed mucosa of patients with IBD.