{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:10:13Z","timestamp":1792638613196,"version":"4.5.0"},"reference-count":157,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004515","name":"Universiti Kebangsaan Malaysia","doi-asserted-by":"crossref","award":["GUP-2023-038"],"award-info":[{"award-number":["GUP-2023-038"]}],"id":[{"id":"10.13039\/501100004515","id-type":"DOI","asserted-by":"crossref"}]},{"award":["GUP-2023-038"],"award-info":[{"award-number":["GUP-2023-038"]}],"id":[{"id":"https:\/\/ror.org\/00bw8d226","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education, Malaysia via the Fundamental Research Grant Scheme","doi-asserted-by":"publisher","award":["FRGS\/1\/2024\/SKK10\/UKM\/01\/2"],"award-info":[{"award-number":["FRGS\/1\/2024\/SKK10\/UKM\/01\/2"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"publisher"}]},{"award":["FRGS\/1\/2024\/SKK10\/UKM\/01\/2"],"award-info":[{"award-number":["FRGS\/1\/2024\/SKK10\/UKM\/01\/2"]}],"id":[{"id":"https:\/\/ror.org\/05mcs2t73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The colonic epithelial barrier is a multilayered defense system comprising the mucus layer, intestinal epithelial cells (IECs), and the underlying lamina propria. These components collectively maintain mucosal homeostasis and restrict microbial translocation. Disruption of this barrier is a hallmark of chronic intestinal inflammation particularly in IBDs, and is primarily driven by pro-inflammatory cytokines, such as TNF-\u03b1, IFN-\u03b3, IL-1\u03b2, and IL-6. TNF-\u03b1 and IFN-\u03b3 synergistically induce epithelial cell apoptosis and tight junction disassembly through mechanisms involving TNFR2 upregulation, myosin light chain kinase (MLCK) activation, and adherens junction destabilization. IL-1\u03b2 amplifies paracellular permeability via NF-\u03baB-dependent MLCK induction and OCLN downregulation, while IL-6 promotes barrier leakiness by upregulating CLDN-2 and sustaining self-reinforcing inflammatory loops that maintain chronic inflammation and impede epithelial repair. This leads to persistent immune-cell infiltration, chronic tight junction remodeling, and failure of barrier replenishment. Consequently, leaky colon facilitates microbial and antigen translocation into the lamina propria, further activating immune cells and perpetuating pro-inflammatory signaling. This review synthesizes current evidence and studies on the cooperative and self-reinforcing roles of pro-inflammatory cytokines, providing insight into the mechanisms underlying chronic intestinal barrier dysfunction and highlighting the need for therapeutic strategies that simultaneously target multiple inflammatory axes to restore barrier integrity in inflammatory bowel disorders.<\/jats:p>","DOI":"10.3390\/ijms27114722","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:45:08Z","timestamp":1779673508000},"page":"4722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pro-Inflammatory Cytokines as Core Mediators of Colonic Epithelial Barrier Dysfunction: Roles of TNF-\u03b1, IFN-\u03b3, IL-1\u03b2, and IL-6"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5171-7907","authenticated-orcid":false,"given":"Dinesh Prasad","family":"V Thanga Velu","sequence":"first","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6449-639X","authenticated-orcid":false,"given":"Mh Busra","family":"Fauzi","sequence":"additional","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8334-6821","authenticated-orcid":false,"given":"Faizul","family":"Jaafar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norfilza Mohd","family":"Mokhtar","sequence":"additional","affiliation":[{"name":"International Medical School, Management and Science University, Shah Alam 40100, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7801-6358","authenticated-orcid":false,"given":"Mohd Helmy","family":"Mokhtar","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adila","family":"A Hamid","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1080\/17474124.2017.1343143","article-title":"The intestinal barrier: A fundamental role in health and disease","volume":"11","author":"Vancamelbeke","year":"2017","journal-title":"Expert Rev. 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