IL-1β/IL-6 inflammatory crosstalk drives DNA methylation and histone remodeling associated with cytokine induced senescence in luminal breast cancer.
6 affiliations
- 1Department of Cellular and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India. [email protected].
- 2Department of Cellular and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
- 3Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- 4SDM Centre for Cellular and Molecular Sciences, SDM College of Medical Sciences and Hospital, Shri Dharmasthala Manjunatheshwara (SDM) University, Dharwad, Karnataka, 580009, India.
- 5Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
- 6SDM Centre for Cellular and Molecular Sciences, SDM College of Medical Sciences and Hospital, Shri Dharmasthala Manjunatheshwara (SDM) University, Dharwad, Karnataka, 580009, India. [email protected].
Abstract
Background
Chronic inflammation exerts paradoxical effects in breast cancer, inducing growth arrest while sustaining tumor progression. However, how autocrine and paracrine inflammatory cytokine induced senescence integrates with tumor-promoting behaviour remains unclear. Here, we identify a reciprocal IL-1β/IL-6 circuit that links inflammatory cues, epigenetic remodeling and cytokine induced senescence in luminal breast cancer cells.Methods
Following treatment with IL-1β and IL-6, MCF-7 cells were examined using cell-cycle, apoptosis, reactive oxygen species flow cytometry assays, and senescence assays; RNA sequencing; global DNA methylation quantification; methylation-specific PCR; ChIP-qPCR for histone marks; cytokine ELISA; and western blotting for DNMTs and STAT3/AKT/NF-κB signaling proteins. The kinetics of IL-1β and IL-6 signaling were examined using receptor antagonism and pharmacological inhibition.Results
IL-1β induced senescence characterized by G₀/G₁ arrest, elevated SA-β-gal activity, ROS accumulation and absence of apoptosis. Transcriptomic profiling revealed cell-cycle regulator repression, enrichment of senescence-associated signatures and a pro-inflammatory secretory phenotype. Mechanistically, IL-1β induced increased DNMT1 and DNMT3A expression, elevated global DNA methylation, induced promoter-specific DNA methylation (IL-15, HMGB2) and histone mark remodeling (IL-6, IL1RN, BCL2,BAX) at inflammatory, senescence, and apoptotic loci. IL-1 receptor antagonism attenuated these effects. IL-6 induced downstream of IL-1β, in turn activated STAT3, increased DNMT1 and DNMT3B expression, amplified IL-1β expression and tumor-promoting phenotypes, while sustaining the IL-1β induced senescence state. IL-6R blockade disrupted this axis and reduced tumor-promoting effects.Conclusion
An IL-1β/IL-6 inflammatory loop drives epigenetic remodeling associated with cytokine induced senescence while promoting tumor-supportive signaling. IL-1β initiates the senescence program, whereas IL-6 reinforces and sustains this state through STAT3/DNMT signaling, highlighting inflammatory cytokine signaling pathways as potential therapeutic targets for breast cancer therapy.
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BibTeX
@article{pereira2026il1βil6,
title = {{IL-1β/IL-6 inflammatory crosstalk drives DNA methylation and histone remodeling associated with cytokine induced senescence in luminal breast cancer.}},
author = {Satyajit Dey Pereira and Kanaka Sai Ram Padam and Padival Shruptha and Aditi Atreya and Manjunath B Joshi and Kapaettu Satyamoorthy},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
year = {2026},
month = oct,
doi = {10.1007/s00011-026-02391-7},
url = {https://europepmc.org/article/MED/42892641},
note = {CC BY},
}
RIS
TY - JOUR
TI - IL-1β/IL-6 inflammatory crosstalk drives DNA methylation and histone remodeling associated with cytokine induced senescence in luminal breast cancer.
AU - Satyajit Dey Pereira
AU - Kanaka Sai Ram Padam
AU - Padival Shruptha
AU - Aditi Atreya
AU - Manjunath B Joshi
AU - Kapaettu Satyamoorthy
PY - 2026
DA - 2026/10/17
JO - Inflammation research : official journal of the European Histamine Research Society ... [et al.]
DO - 10.1007/s00011-026-02391-7
UR - https://europepmc.org/article/MED/42892641
AB - Background Chronic inflammation exerts paradoxical effects in breast cancer, inducing growth arrest while sustaining tumor progression. However, how autocrine and paracrine inflammatory cytokine induced senescence integrates with tumor-promoting behaviour remains unclear. Here, we identify a reciprocal IL-1β/IL-6 circuit that links inflammatory cues, epigenetic remodeling and cytokine induced senescence in luminal breast cancer cells.Methods Following treatment with IL-1β and IL-6, MCF-7 cells were examined using cell-cycle, apoptosis, reactive oxygen species flow cytometry assays, and senescence assays; RNA sequencing; global DNA methylation quantification; methylation-specific PCR; ChIP-qPCR for histone marks; cytokine ELISA; and western blotting for DNMTs and STAT3/AKT/NF-κB signaling proteins. The kinetics of IL-1β and IL-6 signaling were examined using receptor antagonism and pharmacological inhibition.Results IL-1β induced senescence characterized by G₀/G₁ arrest, elevated SA-β-gal activity, ROS accumulation and absence of apoptosis. Transcriptomic profiling revealed cell-cycle regulator repression, enrichment of senescence-associated signatures and a pro-inflammatory secretory phenotype. Mechanistically, IL-1β induced increased DNMT1 and DNMT3A expression, elevated global DNA methylation, induced promoter-specific DNA methylation (IL-15, HMGB2) and histone mark remodeling (IL-6, IL1RN, BCL2,BAX) at inflammatory, senescence, and apoptotic loci. IL-1 receptor antagonism attenuated these effects. IL-6 induced downstream of IL-1β, in turn activated STAT3, increased DNMT1 and DNMT3B expression, amplified IL-1β expression and tumor-promoting phenotypes, while sustaining the IL-1β induced senescence state. IL-6R blockade disrupted this axis and reduced tumor-promoting effects.Conclusion An IL-1β/IL-6 inflammatory loop drives epigenetic remodeling associated with cytokine induced senescence while promoting tumor-supportive signaling. IL-1β initiates the senescence program, whereas IL-6 reinforces and sustains this state through STAT3/DNMT signaling, highlighting inflammatory cytokine signaling pathways as potential therapeutic targets for breast cancer therapy.
SN - 1023-3830
SN - 1420-908X
ER -