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EZH2 Regulates Intestinal Inflammation and Necroptosis Through the JNK Signaling Pathway in Intestinal Epithelial Cells

Digestive Diseases and Sciences volume 64, pages 3518–3527 (2019)Cite this article

Abstract

Background

Inflammatory bowel disease (IBD) is a common disorder of chronic intestinal inflammation that can be caused by the disruption of intestinal immune homeostasis.

Aim

We aimed to evaluate the role of enhancer of zeste homolog 2 (EZH2) in the inflammatory response and explore the association between EZH2 and necroptosis in human epithelial colorectal adenocarcinoma cell lines.

Methods

In both in vitro and in vivo models, expression of EZH2 in intestinal tissues was verified by histology. The expression of inflammatory cytokines in cell lines treated with EZH2 siRNA with or without stimulus was analyzed by quantitative real-time polymerase chain reaction. An intestinal necroptosis cell model was established to elucidate whether EZH2 is involved in necroptosis.

Results

Our present data indicated that EZH2 expression was decreased in in vitro and in vivo models and in patients with inflammatory bowel disease. EZH2 downregulation increased the expression of inflammatory factors, including TNF-α, IL-8, IL-17, CCL5, and CCL20 in a Caco-2 cell model. The JNK pathway was activated with the reduction of EZH2. In the necroptosis model, downregulation of EZH2 was detected with the upregulation of necroptotic markers RIP1 and RIP3. In addition, EZH2 knockdown with siRNA increased p-JNK and p-c-Jun.

Conclusion

Our data suggest that EZH2 plays an important role in the development of intestinal inflammation and necroptosis. Hence, EZH2 could be a potential therapeutic target for IBD.

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Acknowledgements

The authors would like to thank Jie Zhang, Yuwei Zhang and the teachers as well as students of the Laboratory of gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, for helpful technical assistance.

Funding

Supported by the National Natural Science Foundation of China (81600413), co-sponsored project of province and ministry of Zhejiang Province of China under Grant (WKJ-ZJ-1516), and Natural Science Foundation of Zhejiang Province (LQ16H030001).

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  1. Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China

    Xinhe Lou, Huatuo Zhu, Longgui Ning, Chunxiao Li, Sha Li, Haojie Du, Xinxin Zhou & Guoqiang Xu

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  1. Xinhe Lou
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Correspondence to Guoqiang Xu.

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Lou, X., Zhu, H., Ning, L. et al. EZH2 Regulates Intestinal Inflammation and Necroptosis Through the JNK Signaling Pathway in Intestinal Epithelial Cells. Dig Dis Sci 64, 3518–3527 (2019). https://doi.org/10.1007/s10620-019-05705-4

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Keywords

  • EZH2
  • Intestinal inflammation
  • Necroptosis
  • JNK/AP-1 pathway