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Inhibition of CREB-mediated ZO-1 and activation of NF-?B-induced IL-6 by colonic epithelial MCT4 destroys intestinal barrier function.

ABSTRACT: 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-?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-?B p65 nuclear translocation and increased the binding of NF-?B p65 to the promoter of IL-6, which is attributed to MCT4 enhanced NF-?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 ?-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.

SUBMITTER: Zhang S

PROVIDER: S-EPMC6869122 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Inhibition of CREB-mediated ZO-1 and activation of NF-κB-induced IL-6 by colonic epithelial MCT4 destroys intestinal barrier function.

Zhang Shunxian S Xu Wanfu W Wang Hongli H Cao Meiwan M Li Musheng M Zhao Junhong J Hu Yan Y Wang Yaodong Y Li Songyu S Xie Yuanwen Y Chen Guanhua G Liu Ruitao R Cheng Yang Y Xu Zhaohui Z Zou Kejian K Gong Sitang S Geng Lanlan L

Cell proliferation 20190816 6

<h4>Objective</h4>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.<h4>Methods</h4>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 a ...[more]

PMID: 31418947

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Dataset Information

Inhibition of CREB-mediated ZO-1 and activation of NF-?B-induced IL-6 by colonic epithelial MCT4 destroys intestinal barrier function.

Publications

Inhibition of CREB-mediated ZO-1 and activation of NF-κB-induced IL-6 by colonic epithelial MCT4 destroys intestinal barrier function.

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