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Notch和TNF-α信号通路促进OLFM4在肠道上皮细胞中的细胞质积累，并在IBD患者的炎症黏膜中发挥细胞保护作用。

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.

作者信息

Kuno Reiko, Ito Go, Kawamoto Ami, Hiraguri Yui, Sugihara Hady Yuki, Takeoka Sayaka, Nagata Sayaka, Takahashi Junichi, Tsuchiya Mao, Anzai Sho, Mizutani Tomohiro, Shimizu Hiromichi, Yui Shiro, Oshima Shigeru, Tsuchiya Kiichiro, Watanabe Mamoru, Okamoto Ryuichi

机构信息

Department of Gastroenterology and Hepatology, Japan.

Advanced Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

出版信息

Biochem Biophys Rep. 2021 Jan 11;25:100906. doi: 10.1016/j.bbrep.2020.100906. eCollection 2021 Mar.

DOI:10.1016/j.bbrep.2020.100906
PMID:33490652
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7808948/
Abstract

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.

摘要

Notch信号通路在炎症性肠病（IBD）患者的肠上皮细胞（IECs）中被激活，并有助于黏膜再生。我们之前的研究表明，TNF-α和Notch信号通路可能协同促进人IECs中肠干细胞（ISC）标志物OLFM4的表达。在本研究中，我们调查了OLFM4在人IEC系中的基因调控和功能。我们证实TNF-α和Notch协同上调OLFM4的mRNA表达。荧光素酶报告基因检测表明，OLFM4转录受TNF-α和Notch协同作用的调控。在蛋白质水平上，TNF-α和Notch之间的协同作用促进了OLFM4在细胞质中的积累，这在人IECs中具有潜在的抗凋亡特性。对患者来源的组织和类器官的分析一致显示，OLFM4在细胞质中的积累是对NF-κB和Notch激活的反应。人IECs中OLFM4在细胞质中的积累受到Notch和TNF-α协同作用的严格调控。OLFM4在细胞质中的这种积累可能在IBD患者的炎症黏膜中具有细胞保护作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/028c27b1699d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/bfeb63a83ab1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/dce5a9889ad4/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/4f0e8bbe2ebc/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/45e2892f17a2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/028c27b1699d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/bfeb63a83ab1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/dce5a9889ad4/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/4f0e8bbe2ebc/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/45e2892f17a2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e25/7808948/028c27b1699d/gr5.jpg

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