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Digestive Diseases and Sciences

, Volume 63, Issue 10, pp 2593–2603 | Cite as

Dysregulated Up-Frameshift Protein 1 Promotes Ulcerative Colitis Pathogenesis Through the TNFR1-NF-κB/MAPKs Pathway

  • Huatuo Zhu
  • Shujun Huang
  • Min Yue
  • Wenguo Chen
  • Chao Lu
  • Xinhe Lou
  • Chunxiao Li
  • Guodong Shan
  • Hongtan Chen
  • Xiaowei Xu
  • Guoqiang Xu
  • Lihua Chen
Original Article
  • 157 Downloads

Abstract

Background

Ulcerative colitis (UC) is an idiopathic colonic mucosal disease, and its pathogenesis has not been fully understood. Up-frameshift protein 1 (UPF1) is a potential molecule for UC predicted by a computational approach.

Aim

The present study aimed to validate the underlying mechanism of UPF1 in UC.

Methods

UPF1 expression was detected by qRT-PCR, western blotting, and immunohistochemistry in dextran sulfate sodium-induced colitis in mice. To simulate the intestinal inflammation microenvironment, NCM460 human colonic epithelial cells were exposed to a mixture of inflammatory mediators. The potential mechanism involving TNFR1-NF-κB/MAPKs pathway activation was addressed by western blotting, reporter gene assays, and siRNA (siUPF1) or UPF1-expressing plasmid pENTER-transfected cells.

Results

UPF1 was downregulated in colonic epithelial cells of colitic mice, and in vitro, contrary to the mRNA levels of the associated cytokines enhanced in the UPF1 dysregulation group within stimulatory factors, most relevant cytokines were significantly decreased in UPF1 overexpression group. Mechanistically, the increased expression of tumor necrosis factor receptor 1 (TNFR1) was found in NCM460 cells pre-treated with siUPF1, with the activation of IKK/NF-κB and MAPKs pathways, including JNK/AP-1 and P38, but not the ERK1/2 pathway. Moreover, the repression of TNFR1 required the interaction of UPF1 with the promoter.

Conclusion

UPF1, which negatively regulated the transcription of TNFR1, is a novel factor regulating intestinal inflammation. The downregulation of UPF1 activated the TNFR1-dependent NF-κB/MAPKs pathway, and promoting inflammatory responses in colon might act as a causal role in UC.

Keywords

Ulcerative colitis (UC) Up-frameshift mutant 1 (UPF1) Tumor necrosis factor receptor 1 (TNFR1) NF-κB/MAPKs pathway 

Notes

Acknowledgments

The authors would like to thank Prof. Chaohui Yu for critical inputs on the project. The authors would also like to thank Meng Li, Jianghua Chen and the teachers as well as students of the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, for outstanding technical assistance.

Author’s contribution

HTZ, SJH and MY initiated the study and performed the experiments, data analysis, and manuscript writing. WGC supervised the study and revised the manuscript. CL, XHL, CXL, GDS, HTC, and XWX contributed to the experimental design, data analysis, and manuscript revision. GQX and LHC had full access to all the data in the present study and had final responsibility for the decision to submit for publication. All authors have read and approved the manuscript.

Funding

The present study was financially supported by grants from the National Natural Science Foundation of China (No. 81600413) and Natural Science Foundation of Zhejiang Province (LY16H030005).

Compliance with ethical standards

Conflict of interest

The authors declare that no conflicts of interest.

Ethical approval

The study was approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Informed consent was obtained from each subject prior to the study. The maintenance of mice and all animal experimental procedures were conducted in accordance with the National Institutes of Health (NIH) guidelines. All mouse studies were approved by The Animal Care and Use Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University, in accordance with the Chinese guidelines for the care and use of laboratory animals.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Gastroenterology, The First Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouPeople’s Republic of China

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