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Peer-reviewedCC BYInternational Journal of Molecular Sciences

Pro-Inflammatory Cytokines as Core Mediators of Colonic Epithelial Barrier Dysfunction: Roles of TNF-α, IFN-γ, IL-1β, and IL-6

  • Dinesh Prasad V Thanga Velu1
  • Mh Busra Fauzi1
  • Faizul Jaafar2
  • Norfilza Mohd Mokhtar3
  • Mohd Helmy Mokhtar4
  • Adila A. Hamid4
4 affiliations
  1. 1Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia
  2. 2Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia
  3. 3International Medical School, Management and Science University, Shah Alam 40100, Malaysia
  4. 4Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Malaysia
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Abstract

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-α, IFN-γ, IL-1β, and IL-6. TNF-α and IFN-γ 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-1β amplifies paracellular permeability via NF-κB-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.

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Cite

BibTeXRIS
BibTeX
@article{velu2026proinflammatory,
  title = {{Pro-Inflammatory Cytokines as Core Mediators of Colonic Epithelial Barrier Dysfunction: Roles of TNF-α, IFN-γ, IL-1β, and IL-6}},
  author = {Dinesh Prasad V Thanga Velu and Mh Busra Fauzi and Faizul Jaafar and Norfilza Mohd Mokhtar and Mohd Helmy Mokhtar and Adila A. Hamid},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = may,
  doi = {10.3390/ijms27114722},
  url = {https://doi.org/10.3390/ijms27114722},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Pro-Inflammatory Cytokines as Core Mediators of Colonic Epithelial Barrier Dysfunction: Roles of TNF-α, IFN-γ, IL-1β, and IL-6
AU  - Dinesh Prasad V Thanga Velu
AU  - Mh Busra Fauzi
AU  - Faizul Jaafar
AU  - Norfilza Mohd Mokhtar
AU  - Mohd Helmy Mokhtar
AU  - Adila A. Hamid
PY  - 2026
DA  - 2026/05/24
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27114722
UR  - https://doi.org/10.3390/ijms27114722
AB  - 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-α, IFN-γ, IL-1β, and IL-6. TNF-α and IFN-γ 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-1β amplifies paracellular permeability via NF-κB-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.
SN  - 1422-0067
SN  - 1661-6596
ER  -