Listerine® attenuates cytokine-induced inflammation and activates zinc–metallothionein responses in gingival fibroblasts

Gingival fibroblasts amplify periodontal inflammation by producing chemokines in response to pro-inflammatory cytokines. Mouth rinses directly contact the gingival tissues, yet their effects on host inflammatory signaling remain incompletely defined. This study investigated how a zinc-containing Listerine® formulation modulates IL-1β/TNF-α–induced responses in human gingival fibroblasts and compared these effects with zinc alone. Primary human gingival fibroblasts were stimulated with IL-1β and TNF-α in the presence or absence of Listerine®. Global transcriptional changes were analyzed by RNA sequencing and validated by quantitative PCR. CXCL8 secretion was quantified by immunoassay. Zinc ions and individual essential oil components were tested separately. Metal content was determined by inductively coupled plasma–mass spectrometry. IL-1β/TNF-α induced a broad inflammatory transcriptional program, including chemokines and innate immune–associated genes. Co-treatment with Listerine® consistently reduced the magnitude of cytokine-induced gene expression while preserving inducibility, indicating quantitative attenuation rather than suppression. Listerine® significantly decreased cytokine-induced CXCL1, CXCL2, and CXCL8 mRNA levels and reduced CXCL8 protein release. Transcriptomic profiling revealed strong induction of metallothionein family members. Zinc was identified as the predominant metal at biologically relevant concentrations. Zinc alone robustly induced metallothioneins but did not significantly reduce cytokine-induced chemokine expression. Individual essential oil components did not reproduce the inhibitory effect. Taken together, Listerine® constrains cytokine-driven inflammatory output in gingival fibroblasts while activating a zinc-associated metallothionein stress response. Zinc alone is insufficient to explain the anti-inflammatory phenotype, supporting a formulation-dependent host-modulating effect.