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Activation of the IL-15/NF-κB Pathway Promotes Cytokine-Induced Cellular Stress and Apoptosis in Celiac Disease Models

Ji-Hoon Park 1, Min-Seo Kim 2, Dae-Won Lee 3, Soo-Jin Han ORCID 4

1Department of Gastroenterology and Hepatology, Seoul National University College of Medicine, Seoul, South Korea.
2Division of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea.
3Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea.
4Center for Intestinal Immunology and Cell Injury Research, Sungkyunkwan University School of Medicine, Suwon, South Korea.

DOI: 10.18081/2378-5225/15.19  
Cited by 0

 Article history: Received 11 November 2025 · Revised 23 December 2025 · Accepted 23 January 2026 · Published 05 February 2026

© 2026 Han, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). 

CC BY 4.0                                                                                                   

Abstract

Background: Celiac disease (CD) is a chronic immune-mediated enteropathy characterized by gluten-induced intestinal epithelial injury. While adaptive immune responses to gliadin are well established, the contribution of cytokine-driven cellular stress pathways remains incompletely understood. Interleukin-15 (IL-15), a key pro-inflammatory cytokine overexpressed in CD, has been implicated in epithelial damage; however, its mechanistic interaction with nuclear factor-κB (NF-κB) signaling and downstream cellular injury pathways requires further elucidation.

Objective: This study aimed to investigate the role of the IL-15/NF-κB signaling axis in mediating oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis in experimental models of celiac disease.

Methods: Human intestinal epithelial cell lines (Caco-2 and HT-29) were exposed to pepsin–trypsin-digested gliadin (PT-gliadin) in the presence or absence of IL-15. NF-κB pathway involvement was assessed using pharmacological inhibition and gene silencing approaches. Cellular stress responses were evaluated through the measurement of reactive oxygen species (ROS), lipid peroxidation (MDA), glutathione (GSH) levels, and ER stress markers (GRP78, CHOP, and ATF4). Apoptosis was quantified using Annexin V/PI flow cytometry, caspase activity assays, and TUNEL staining. An in vivo murine model of gliadin-induced enteropathy was used to validate findings through histopathological and immunohistochemical analyses.

Results: Co-exposure to IL-15 and gliadin significantly reduced epithelial cell viability and increased cytotoxicity compared to gliadin alone (p < 0.001). This effect was associated with marked activation of NF-κB signaling, evidenced by increased phosphorylation of IκBα and nuclear translocation of p65. Enhanced NF-κB activity correlated with elevated ROS production, increased MDA levels, and depletion of GSH, indicating oxidative stress. Concurrently, ER stress was amplified, with significant upregulation of GRP78, CHOP, and ATF4. Apoptotic cell death was markedly increased, involving activation of both intrinsic and extrinsic pathways. In vivo, IL-15 exacerbated intestinal injury, leading to severe villous atrophy and increased expression of NF-κB and cleaved caspase-3. Importantly, inhibition of NF-κB or neutralization of IL-15 significantly attenuated these effects.

Conclusion: The IL-15/NF-κB signaling pathway plays a central role in amplifying gliadin-induced epithelial injury by integrating inflammatory signaling with oxidative stress, ER stress, and apoptosis. Targeting this pathway may represent a promising therapeutic strategy for mitigating intestinal damage in celiac disease and related inflammatory disorders.

Keywords: Celiac disease; IL-15; NF-κB; oxidative stress; endoplasmic reticulum stress; apoptosis; intestinal epithelial injury.

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BM-Publisher · Pathophysiology of Cell Injury Journal (PCIJ) · E-ISSN 2378-5225 · DOI Prefix 10.18081/pcij/2378-5225

Pathophysiology of Cell Injury Journal (PCIJ)
E-ISSN 2378-5225 · Biannual
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Vol 15, Issue 1 (February 2026), pp. 19–36

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Park JH, Kim MS, Lee DW, Han SJ. Activation of the IL-15/NF-κB Pathway Promotes Cytokine-Induced Cellular Stress and Apoptosis in Celiac Disease Models. Pathophysiology of Cell Injury Journal (PCIJ). 2026;15(1):18–36. doi: 10.18081/2378-5225/15.18.

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