ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
This article is part of the Research TopicContextual inflammation: mechanisms of immune adaptation across tissues, time, and disease statesView all articles
Long-term memory in epithelia: transient IFNγ exposure drives stable repression of TFF1 in gastric epithelial cells via epigenetic changes
Provisionally accepted
Antonia Voli1
Daniela Eletto1
Fatima Maria Mentucci1
Chiara Centrella1Martina Pannetta1
Francesco Boccellato2Alfonso Finizio3
Silvana Morello1
Caterina Giraulo1
Amalia Porta1*
Alessandra Tosco1*- 1University of Salerno, Fisciano, Italy
- 2Ludwig Institute for Cancer Research Oxford Branch, Oxford, United Kingdom
- 3Centro Trasfusionale, Ospedale S. Maria della Speranza, Battipaglia, Italy
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Interferon-gamma (IFNγ) is a transiently produced pro-inflammatory cytokine, which activates short-lived JAK–STAT1 signaling but can also induce long-term transcriptional changes. During Helicobacter pylori infection, IFNγ persists in the gastric environment, contributing to both host defense and epithelial injury that promotes tumorigenesis. Although long-term memory of IFNγ has been described in immune cells, its role in gastric epithelial reprogramming during Helicobacter pylori infection remains unexplored. Here, we show that brief IFNγ exposure in gastric epithelial cells causes stable repression of TFF1, a gastric tumor suppressor often lost in H. pylori-associated cancer. Notably, this repression extends after cytokine removal and is driven by the IFNγ-responsive transcription factor C/EBPβ. Mechanistically, TFF1 silencing is linked to chromatin remodeling, including altered phosphorylation of histone H3S10 and acetylation of H3K9 at the TFF1 locus. Inhibition of DNA methylation prevents TFF1 downregulation and C/EBPβ upregulation, indicating that de novo methylation stabilizes the silenced state. Similarly, inflammatory mediators released by H. pylori-activated immune cells replicate this effect in primary gastric mucosoids, where TFF1 repression extends after cytokine removal. Overall, our findings show that transient inflammatory signals cause durable gene silencing through epigenetic remodeling, revealing how chronic inflammation can reprogram epithelial cells and promote cancer, while suggesting strategies to reverse these effects.
Keywords: gastric mucosoids, Helicobacter, IFNγ, Long-term memory, TFF1
Received: 23 Oct 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 Voli, Eletto, Mentucci, Centrella, Pannetta, Boccellato, Finizio, Morello, Giraulo, Porta and Tosco. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Amalia Porta
Alessandra Tosco
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