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UBE2W Improves the Experimental Colitis by Inhibiting the NF-κB Signaling Pathway

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Abstract

Background

The NF-κB signaling cascade regulates immune response and is often dysregulated in tumor development. UBE2W is a novel type I ubiquitin-conjugating enzyme (E2) whose biological function is still unclear.

Aims

This study was designed to investigate whether UBE2W regulates NF-κB signaling pathway and is involved in the progression of experimental colitis.

Methods

At the cellular level, the effect of UBE2W on NF-κB transcriptional activity was measured using a dual-luciferase reporter assay. The influence of UBE2W on NF-κB pathway activation and the entry of p65 into the nucleus were determined by Western blot and immunofluorescence analyses, respectively. Moreover, the colitis model was established by administering 2.5% dextran sulfate sodium (DSS)/water to UBE2W overexpression, UBE2W-knockdown and control mice. Body weight, stool consistency, colon length and clinical severity were examined. Expression of pro-inflammatory cytokines and phosphorylation of p65 and IκB in the colon tissue were measured by qRT-PCR and Western blot, respectively.

Results

UBE2W inhibited TNFα-induced NF-κB transcription activity, attenuated IκB and p65 phosphorylation, downregulated TNFα and IL-8 expression and blocked the entry of p65 into the nucleus. In the DSS-induced colitis model, UBE2W-knockdown mice had increased weight loss, more serious diarrhea and mucosal injures compared with the control mice. Moreover, phosphorylation of IκB and p65 and the expression of pro-inflammatory mediators such as TNFα, IL-6 were significantly increased in UBE2W knockdown mice. However, these changes were completely reversed in UBE2W overexpression mice.

Conclusions

The overexpression of UBE2W ameliorates the severity of DSS-induced colitis, which may be mediated by inhibiting the expression of pro-inflammatory mediators and activation of the NF-κB signaling pathway. These findings provide evidence that UBE2W might have potential therapeutic implications in IBD.

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Abbreviations

UBE2W:

Ubiquitin-conjugating enzyme E2W

DDS:

Dextran sulfate sodium

NF-κB:

Nuclear factor-κB

TNFα:

Tumor necrosis factor α

IL-6:

Interleukin-6

COX2:

Cyclooxygenase-2

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Acknowledgments

We thank Pro. HuiYan Li of the National Biomedical Analysis Center for this project guidance.

Funding

This work was supported by grants from National Natural Science Foundation of China (Nos.31600624).

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Authors and Affiliations

  1. Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China

    Shaoxin Wang, Jiang Pu, Xiaowei Li, Zhihui Yan, Chao Li, Yan Zheng, Zhe Luo & Lihong Cui

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  1. Shaoxin Wang
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  2. Jiang Pu
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Correspondence to Lihong Cui.

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Wang, S., Pu, J., Li, X. et al. UBE2W Improves the Experimental Colitis by Inhibiting the NF-κB Signaling Pathway. Dig Dis Sci 67, 5529–5539 (2022). https://doi.org/10.1007/s10620-022-07453-4

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  • DOI: https://doi.org/10.1007/s10620-022-07453-4

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