Interleukin-6 Modulation of Intestinal Epithelial Tight Junction Permeability Is Mediated by JNK Pathway Activation of Claudin-2 Gene
Open accessAbstract
Defective intestinal epithelial tight junction (TJ) barrier has been shown to be a pathogenic factor in the development of intestinal inflammation. Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine which plays an important role in promoting inflammatory response in the gut and in the systemic circulation. Despite its key role in mediating variety inflammatory response, the effect of IL-6 on intestinal epithelial barrier remains unclear. The purpose of this study was to investigate the effect of IL-6 on intestinal epithelial TJ barrier and to delineate the intracellular mechanisms involved using in-vitro (filter-grown Caco-2 monolayers) and in-vivo model (mouse intestinal perfusion) systems. Our results indicated that IL-6 causes a site-selective increase in Caco-2 intestinal epithelia TJ permeability, causing an increase in flux of small-sized molecules having molecular radius <4 Å. The size-selective increase in Caco-2 TJ permeability was regulated by protein-specific increase in claudin-2 expression. The IL-6 increase in TJ permeability required activation of JNK signaling cascade. The JNK pathway activation of AP-1 resulted in AP-1 binding to its binding sequence on the claudin-2 promoter region, leading to promoter activation and subsequent increase in claudin-2 gene transcription and protein synthesis and TJ permeability. Our in-vivo mouse perfusion showed that IL-6 modulation of mouse intestinal permeability was also mediated by AP-1 dependent increase in claudin-2 expression. In conclusion, our studies show for the first time that the IL-6 modulation of intestinal TJ permeability was regulated by JNK activation of AP-1 and AP-1 activation of claudin-2 gene.
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Increased serum concentrations of TNF, IL-1β, and IL-6 are potent inducers of intestinal permeability.
“Increased serum concentrations of TNF, IL-1β, and IL-6 have also been shown to be potent inducers of intestinal permeability50–53.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [50]
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- Authors
- Al-Sadi, R., Ye, D., Boivin, M., Guo, S., Hashimi, M., Ereifej, L., & Ma, T. Y.
- Affiliations
- University of New Mexico (US)
- Corresponding author
- Ye, Dongmei
- Boivin, Michel
- Guo, Shuhong
- Hashimi, Mariam
- Ereifej, Lisa
- Ma, Thomas Y.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-03-24
- Volume
- 9
- Issue
- 3
- Pages
- e85345
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3963839
- OpenAlex
- W2126506597
- Cited by
- 280
- References
- 43
- Citations by year
- 2026: 22 · 2025: 24 · 2024: 26 · 2023: 31 · 2022: 29 · 2021: 35 · 2020: 17 · 2019: 26 · 2018: 21 · 2017: 19 · 2016: 18 · 2015: 12
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Veterans Affairs
- National Institute of Diabetes and Digestive and Kidney Diseases (R0 1-DK-81429-03, R01DK081429, RO 1-DK-81429)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- interleukin-6, claudin-2, JNK signaling, AP-1 transcription factor, intestinal epithelial barrier, intestinal inflammation, Caco-2 cell monolayers, intestinal permeability, size-selective permeability
- MeSH terms
- Animals, Humans, Intestinal Mucosa, Permeability, Transcriptional Activation, Interleukin-6, Transcription Factor AP-1, Caco-2 Cells, Tight Junctions, MAP Kinase Signaling System, Intracellular Space, JNK Mitogen-Activated Protein Kinases, Mice, Claudin-2
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