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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
- Source :
- Cell Proliferation
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
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‐κB‐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‐κB p65 nuclear translocation and increased the binding of NF‐κB p65 to the promoter of IL‐6, which is attributed to MCT4 enhanced NF‐κB‐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 α‐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.
- Subjects :
- Monocarboxylic Acid Transporters
0301 basic medicine
Colon
Muscle Proteins
CREB
Epithelium
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
inflammatory bowel disease
In vivo
Humans
Luciferase
Intestinal Mucosa
Interleukin 6
Barrier function
ZO‐1
biology
Interleukin-6
Tumor Necrosis Factor-alpha
Chemistry
nuclear factor‐κB
NF-kappa B
Transcription Factor RelA
NF-κB
Original Articles
IL‐6
Cell Biology
General Medicine
monocarboxylate transporter 4
030104 developmental biology
030220 oncology & carcinogenesis
Zonula Occludens-1 Protein
Monocarboxylate transporter 4
biology.protein
Cancer research
Original Article
Ectopic expression
Caco-2 Cells
Subjects
Details
- ISSN :
- 13652184 and 09607722
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Cell Proliferation
- Accession number :
- edsair.doi.dedup.....3609488b05dfa433ea4ca882a2e4c646