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TNF-α Modulation of Intestinal Epithelial Tight Junction Barrier Is Regulated by ERK1/2 Activation of Elk-1
Open accessAbstract
Tumor necrosis factor (TNF-α) is a proinflammatory cytokine that plays a critical role in the pathogenesis of inflammatory bowel disease. TNF-α causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of MAP kinase pathways (ERK1/2 and p38 kinase) and the molecular processes involved. An in vitro intestinal epithelial model system consisting of Caco-2 monolayers and an in vivo mouse model system were used to delineate the cellular and molecular mechanisms involved in TNF-α effects on tight junction barrier. The TNF-α-induced increase in Caco-2 tight junction permeability was mediated by activation of the ERK1/2 signaling pathway, but not the p38 kinase pathway. Activation of the ERK1/2 pathway led to phosphorylation and activation of the ETS domain-containing transcription factor Elk-1. The activated Elk-1 translocated to the nucleus, where it bound to its binding motif on the myosin light chain kinase (MLCK) promoter region, leading to the activation of MLCK promoter activity and gene transcription. In addition, in vivo intestinal perfusion studies also indicated that the TNF-α-induced increase in mouse intestinal permeability requires ERK1/2-dependent activation of Elk-1. These studies provide novel insight into the cellular and molecular processes that regulate the TNF-α-induced increase in intestinal epithelial tight junction permeability.
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“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 [53]
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Metadata
- Authors
- Al-Sadi, R., Guo, S., Ye, D., & Ma, T. Y.
- Affiliations
- University of New Mexico (US)
- Corresponding author
- Ma, Thomas Y.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 183
- Issue
- 6
- Pages
- 1871-1884
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC5745548
- OpenAlex
- W1964163204
- Cited by
- 262
- References
- 48
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 23 · 2023: 22 · 2022: 29 · 2021: 36 · 2020: 24 · 2019: 20 · 2018: 22 · 2017: 17 · 2016: 14 · 2015: 10 · 2014: 5 · 2013: 1
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (R01-DK081429, R01-DK064165)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- TNF-α, tight junction barrier function, intestinal permeability, ERK signaling, Elk-1, p38 MAPK, myosin light chain kinase, Caco-2 cell monolayers, inflammatory bowel disease, MAPK signaling
- MeSH terms
- Animals, Cell Nucleus, Enzyme Activation, Humans, Intestinal Mucosa, Myosin-Light-Chain Kinase, Permeability, Promoter Regions, Genetic, Transcription, Genetic, Tumor Necrosis Factor-alpha, Caco-2 Cells, Tight Junctions, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, Active Transport, Cell Nucleus, Mitogen-Activated Protein Kinase 3, ets-Domain Protein Elk-1, Mice
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