Journal
CELL PROLIFERATION
Volume 52, Issue 6, Pages -Publisher
WILEY
DOI: 10.1111/cpr.12673
Keywords
CREB; IL-6; inflammatory bowel disease; monocarboxylate transporter 4; nuclear factor-kappa B; ZO-1
Categories
Funding
- National Natural Science Foundation of China [81770552, 81860101]
- Natural Science Foundation of Guangdong Province [2017A030313838, 2018A0303130175]
- Medical Science and Technology Foundation of Guangdong [A2018395, A2019534]
- Guangzhou Municipal Science and Technology Project [201804010148, 907171491046, 201904010485]
- Guangzhou Municipal Health and Family Planning Commission [20191A010024]
- China Postdoctoral Science Foundation [2018M643043]
- Postdoctoral Research Funding of Guangzhou Women and Children's Medical Center [5001-3001075]
- Funding of Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center [IP-2016-005, IP-2018-009, Pre-NSFC-2019-005]
- Guangzhou Women and Children's Medical Center [201704020223]
- Natural Science Foundation of Hainan Province [2819QN372]
- Sun Yat-Sen University [201704020223]
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Objective Inflammatory bowel disease (IBD) is a disorder intestinal inflammation and impaired barrier function, associated with increased epithelial expression of monocarboxylate transporter 4 (MCT4). However, the specific non-metabolic function and clinical relevance of MCT4 in IBD remain to be fully elucidated. Methods Lentivirus-mediated overexpression of MCT4 was used to assess the role of MCT4 in transcriptionally regulating ZO-1 and IL-6 expression by luciferase assays, WB and ChIP. IP was used to analyse the effect of MCT4 on the interaction NF-kappa B-CBP or CREB-CBP, and these MCT4-mediated effects were confirmed in vivo assay. Results We showed that ectopic expression of MCT4 inhibited ZO-1 expression, while increased pro-inflammatory factors expression, leading to destroy intestinal epithelial barrier function in vitro and in vivo. Mechanistically, MCT4 contributed NF-kappa B p65 nuclear translocation and increased the binding of NF-kappa B p65 to the promoter of IL-6, which is attributed to MCT4 enhanced NF-kappa B-CBP interaction and dissolved CREB-CBP complex, resulting in reduction of CREB activity and CREB-mediated ZO-1 expression. In addition, treatment of experimental colitis with MCT4 inhibitor alpha-cyano-4-hydroxycinnamate (CHC) ameliorated mucosal intestinal barrier function, which was due to attenuation of pro-inflammation factors expression and enhancement of ZO-1 expression. Conclusion These findings suggested a novel role of MCT4 in controlling development of IBD and provided evidence for potential targets of IBD.
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