Mesalamine and azathioprine modulate junctional complexes and restore epithelial barrier function in intestinal inflammation
Open accessAbstract
Disruption of mucosal structure and barrier function contribute to the pathogenesis of inflammatory bowel disease (IBD). Efficacy of therapy in IBD is based on endoscopic mucosal healing, which occurs by a dynamic interplay of epithelial cell regeneration, migration and differentiation. Both mesalamine (5-ASA) and azathioprine (AZTP) promote this process through mechanisms not clearly understood. We examined molecular pathways implicated in epithelial barrier function that were altered by 5-ASA and AZTP. Paracellular permeability induced by inflammatory mediators was mitigated by both compounds through restoration of cellular anchoring complexes. 5-ASA and AZTP induced rearrangement and membranous localization of junctional proteins and modulated genes involved in tight junctions. Intestinal organoids from wildtype-mice treated with TNF-α and IL-10- deficient-mice displayed impaired epithelial barrier with loss of membranous E-cadherin and reduced Desmoglein-2 expression. These effects were counteracted by 5-ASA and AZTP. Unlike AZTP that exhibited antiproliferative effects, 5-ASA promoted wound healing in colon epithelial cells. Both affected cellular senescence, cell cycle distribution and restricted cells in G1 or S phase without inducing apoptosis. This study provides mechanistic evidence that molecular actions of 5-ASA and AZTP on intestinal epithelia are fundamental in the resolution of barrier dysfunction.
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Conventional treatment strategies include the use of immunosuppressants such as azathioprine and mesalamine that are used in the clinic to treat ulcerative colitis and Crohn's disease.
“Conventional treatment strategies include the use of immunosuppressants such as azathioprine and mesalamine that are used in the clinic to treat ulcerative colitis and Crohn's disease.188”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [188]
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- [29]Khare V Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1 Biochemical pharmacology 2013 85 234 244 10.1016/j.bcp.2012.10.026 23146664 PMC3557386 · DOI
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- Authors
- Khare, V., Krnjic, A., Frick, A., Gmainer, C., Asboth, M., Jimenez, K., Lang, M., Baumgartner, M., Evstatiev, R., & Gasche, C.
- Affiliations
- Medical University of Vienna (AT)
- ORCID
- Venue
- Scientific Reports
- Published
- 2019-02-26
- Volume
- 9
- Issue
- 1
- Pages
- 2842-2842
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6391397
- OpenAlex
- W2916392843
- Cited by
- 70
- References
- 48
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 7 · 2022: 9 · 2021: 12 · 2020: 4 · 2019: 6 · 2017: 1
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Austrian Science Fund (P 27681, I 1573)
- ERA-NET
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- 5-aminosalicylic acid, azathioprine, inflammatory bowel disease, intestinal epithelial barrier, tight junctions, paracellular permeability, E-cadherin, desmoglein 2, intestinal organoids, TNF-α, IL-10 deficiency, epithelial repair, cellular senescence, cell cycle, mucosal healing
- MeSH terms
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Azathioprine, Colitis, Epithelial Cells, Inflammation, Intestines, Wound Healing, Inflammatory Bowel Diseases, Mesalamine, Mice
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