Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation
Open accessAbstract
Background: Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear. Aims: The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system. Results: MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis. Conclusion: Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.
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The complex signaling pathway at the blood/CNS interface is constituted by the sequence of selectins, chemokines and integrins, resulting in emperipolesis through matrix metalloproteinases type 9 (MMP9) activation and tight-junctions disruption.
“Thus, the complex signaling pathway is constituted by the sequence of selectins, chemokines and integrins at the interface blood/CNS, resulting in emperipolesis through matrix metalloproteinases type 9 (MMP9) activation and tight-junctions disruption [74,75].”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [75]
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- Authors
- Al-Sadi, R., Engers, J., Haque, M., King, S., Al-Omari, D., & Ma, T. Y.
- Affiliations
- Pennsylvania State University (US)
- University of New Mexico (US)
- Corresponding author
- Engers, Jessica
- Haque, Mohammad
- King, Steven
- Al-Omari, Deemah
- Ma, Thomas Y.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2021-04-07
- Volume
- 16
- Issue
- 4
- Pages
- e0249544
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC8026081
- OpenAlex
- W3144084593
- Cited by
- 93
- References
- 95
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 22 · 2023: 14 · 2022: 13 · 2021: 3
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Crohn's and Colitis Foundation of America (326502)
- Penn State College of Medicine
- National Institute of Diabetes and Digestive and Kidney Diseases (R0-1-DK-106072-01, R01-DK-121073-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- MMP-9, NF-κB p65, intestinal permeability, inflammatory bowel disease, myosin light chain kinase, interleukin-8, Caco-2 cells, NF-κB nuclear translocation, intestinal epithelial barrier dysfunction
- MeSH terms
- Cell Membrane Permeability, Gene Expression Regulation, Humans, Intestinal Mucosa, Models, Biological, Myosin-Light-Chain Kinase, Inflammatory Bowel Diseases, Interleukin-8, NF-kappa B, Caco-2 Cells, Tight Junctions, Matrix Metalloproteinase 9
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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