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Tumor necrosis factor α-induced protein 3 (A20) is dysregulated in pediatric Crohn disease

Authors Zaidi D, Huynh HQ, Carroll MW, Baksh S, Wine E

Received 3 August 2017

Accepted for publication 12 December 2017

Published 30 May 2018 Volume 2018:11 Pages 217—231


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Wing-Kin Syn

Deenaz Zaidi,1,2 Hien Q Huynh,1 Matthew W Carroll,1 Shairaz Baksh,1,3,4 Eytan Wine1,2,5

1Department of Pediatrics, 2Department of Medicine, Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR), 3Department of Biochemistry, 4Department of Oncology, Cancer Institute of Northern Alberta (CRINA), 5Department of Physiology, University of Alberta, Edmonton, AB, Canada

Purpose: A significant feature of pediatric inflammatory bowel diseases (IBD), which include Crohn disease (CD), and ulcerative colitis (UC), is failure to suppress inflammation. The inability to regulate inflammation renders a major challenge toward establishing effective treatments in IBD. Nuclear factor kappa-light-chain-enhancer of activated B-cells-induced inflammation is inhibited by A20 through interactions with TAX1BP1 (Tax1-binding protein 1) and A20-binding inhibitor of NF-κβ activation (ABIN)-1 (A20 binding and inhibitor of NF-κβ) and upon phosphorylation by inhibitor of nuclear factor kappa-β kinase subunit beta (IKKβ), which stabilizes it. We hypothesized that dysregulation of A20 is an important factor in uncontrolled inflammation in pediatric IBD.
Patients and methods: Gene expression of A20, IKKβ, ABIN-1, TAX1BP1, A20 protein, cytokine levels, and A20 phosphorylation was analyzed in the terminal ileum (TI) of 39 patients (14 non-IBD, 15 CD, and 10 UC). A20 expression and protein in T-84 cells and ex vivo biopsies of patients were measured after treatment with Escherichia coli strains or tumor necrosis factor (TNF)-α.
Results: TNF-α levels and A20 expression were increased in the TI of CD patients. A20 protein levels and ABIN-1 expression were low, TAX1BP1 expression was high, and IKKβ was unchanged. A20 expression positively correlated with biopsy TNF-α levels and inflammatory markers in CD patients. A20 phosphorylation appeared lower in CD patients. A20 expression in TI biopsies from CD patients and T84 cells was triggered with E. coli, strain LF82, while A20 protein levels remained unchanged.
Conclusion: We describe a potential mechanism related to failure of A20 to suppress inflammation in CD, characterized by high A20 expression and low A20 protein levels. The dysregulation of A20 is potentially due to alterations in ABIN-1, and infection with E. coli strain LF82 could affect the function and stability of A20. Our study signifies an important finding in A20 regulation in IBD, which prevents it from suppressing inflammation.

Keywords: A20, ABIN-1, inflammation, NF-κβ, TAX1BP1, E. coli

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