IL-1β/IL-6 inflammatory crosstalk drives DNA methylation and histone remodeling associated with cytokine induced senescence in luminal breast cancer
Year: 2026
Type: article
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 G 0 /G 1 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.
Source: Inflammation Research
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
OpenAlex ID: W7222803794