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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

39 Pages Posted: 23 Jan 2019

See all articles by Shunxian Zhang

Shunxian Zhang

Guangzhou Medical University - Guangzhou Institute of Pediatrics

Wanfu Xu

Guangzhou Medical University - Guangzhou Institute of Pediatrics

Hongli Wang

Guangzhou Medical University - Department of Gastroenterology

Musheng Li

Guangzhou Medical University

Kejian Zou

Hainan General Hospital

Yan Hu

Hainan General Hospital

Yaodong Wang

Nanjing University of Chinese Medicine (NJUCM)

Meiwan Cao

Guangzhou Medical University - Guangzhou Institute of Pediatrics

Yang Cheng

Guangzhou Medical University - Guangzhou Institute of Pediatrics

Sitang Gong

Guangzhou Medical University - Department of Gastroenterology; Guangzhou Medical University - Guangzhou Women and Children's Medical Center; Guangzhou Medical University - Digestive Department

Lanlan Geng

Guangzhou Medical University - Guangzhou Women and Children's Medical Center; Guangzhou Medical University - Guangzhou Institute of Pediatrics

More...

Abstract

Background: Inflammatory bowel disease(IBD) is characterized by intestinal inflammation and impaired barrier function, associated with increased epithelial expression of monocarboxylate Transporter 4 (MCT4).

Methods: we performed qPCR, IF, WB and utilized luciferase, and ChIP to analyze MCT4 on NF-κB and CREB activity and DNA binding in IECs. IP was used to analyze the effect of MCT4 on the interaction NF-κB-CBP or CREBCBP. In vivo assay were detected by IF, WB and to analyze the role and mechanism of MCT4 in IBD.

Findings: Functional studies further showed that ectopic expression of MCT4 disrupted tight junction protein 1(ZO-1) expression and increased pro-inflammatory factors expression, leading to destroy intestinal epithelial barrier function in vitro and in vivo. Mechanistically, one hand, MCT4 led to nuclear translocation of p65 and increased the binding of NF-κB p65 to the promoter of IL-6, on the other hand, MCT4 suppressed cAMP-response element binding protein (CREB) activity and reduced CREBmediated ZO-1 expression. these effect were attributed to MCT4 contributed to NF-κB-CBP interaction, while dissolved CREB-CBP complex. Treatment of experimental colitis with MCT4 inhibitor by α-cyano-4- hydroxycinnamate (CHC) significantly ameliorated mucosal intestinal barrier function in vivo, which was attributed to attenuation of proinflammation factors expression and enhancement of ZO-1 expression.

Interpretation: These findings suggested a novel MCT4 role in controlling development of IBD, which could serve as a new therapeutic target of IBD.

Funding Statement: This work was supported by National Natural Science Foundation of China (No.81770552, No.81860101), Natural Science Foundation of Guangdong (No.2017A030313838, No.2018A0303130175), Medical Science and Technology Foundation of Guangdong (No.A2018395), Science and Technology plan program of Guangzhou (No.201804010148), General program of Guangzhou Health and plan commission (No.805150202068), Postdoctoral Research Funding of Guangzhou Women and Children’s Medical Center (NO.5001-3001075), Funding of Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center (NO.IP-2016-005, NO.IP2018-009).

Declaration of Interests: The authors declared that they have no competing interests.

Ethics Approval Statement: Human study: Based on the declaration of Helsinki as reflected in a prior approval by the institution’s human research committee, this study was conducted in a cohort of 54 patients with inflammatory bowel disease (IBD) and 16 healthy control in Guangzhou Women and Children’s Medical Center from 2016 to 2018 approved by the Medical Ethical Review Board(2017030602).

Animal study: All animal experiments were approved by the Guangzhou Women and Children’s Medical Center animal care and use committee.

Keywords: MCT4; CREB; ZO-1; NF-κB; IL-6; IBD

Suggested Citation

Zhang, Shunxian and Xu, Wanfu and Wang, Hongli and Li, Musheng and Zou, Kejian and Hu, Yan and Wang, Yaodong and Cao, Meiwan and Cheng, Yang and Gong, Sitang and Geng, Lanlan, Inhibition of CREB-Mediated ZO-1 and Activation of NF-κB-Induced IL-6 by Colonic Epithelial MCT4 Destroys Intestinal Barrier Function (January 16, 2019). Available at SSRN: https://ssrn.com/abstract=3320131

Shunxian Zhang

Guangzhou Medical University - Guangzhou Institute of Pediatrics

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510000
China

Wanfu Xu (Contact Author)

Guangzhou Medical University - Guangzhou Institute of Pediatrics ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510000
China

Hongli Wang

Guangzhou Medical University - Department of Gastroenterology

Guangzhou
China

Musheng Li

Guangzhou Medical University

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510080
China

Kejian Zou

Hainan General Hospital

Haikou, 570311
China

Yan Hu

Hainan General Hospital

Haikou, 570311
China

Yaodong Wang

Nanjing University of Chinese Medicine (NJUCM)

Nanjing, 210023
China

Meiwan Cao

Guangzhou Medical University - Guangzhou Institute of Pediatrics

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510000
China

Yang Cheng

Guangzhou Medical University - Guangzhou Institute of Pediatrics

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510000
China

Sitang Gong

Guangzhou Medical University - Department of Gastroenterology ( email )

Guangzhou
China

Guangzhou Medical University - Guangzhou Women and Children's Medical Center ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou, Guangdong Sheng 510000
China

Guangzhou Medical University - Digestive Department ( email )

Guangdong
China

Lanlan Geng

Guangzhou Medical University - Guangzhou Women and Children's Medical Center ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou, Guangdong Sheng 510000
China

Guangzhou Medical University - Guangzhou Institute of Pediatrics ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510000
China

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