Bruton's tyrosine kinase modulates IL-1β-induced cytokine and matrix metalloproteinase expression in human gingival fibroblasts

Objective: Periodontitis is a chronic inflammatory disease characterized by destruction of periodontal connective tissues driven by dysregulated host responses. Interleukin-1β (IL-1β) plays a central role in periodontal inflammation by inducing matrix metalloproteinases (MMPs) and pro-inflammatory cytokines in gingival fibroblasts. Although Bruton's tyrosine kinase (BTK) is known to regulate inflammatory signaling in immune cells, its role in gingival fibroblasts remains unclear. This study investigated the role of BTK in IL-1β–induced inflammatory and catabolic responses in human gingival fibroblasts (HGFs). Design: HGFs were stimulated with IL-1β in the presence or absence of BTK inhibitors (ibrutinib and CNX-774) or following BTK-specific siRNA transfection. Expression of MMPs and cytokines was analyzed by real-time PCR, western blotting, and ELISA. Signaling pathways were evaluated by assessing phosphorylation of TAK1 and MAPKs and activation of AP-1 and NF-κB. Results: IL-1β markedly increased the expression and secretion of MMP-1 and MMP-3, as well as TNF-α, IL-6, and IL-8 in HGFs. Pharmacological inhibition or genetic silencing of BTK significantly attenuated these responses without affecting cell viability. Mechanistically, BTK inhibition suppressed IL-1β–induced phosphorylation of TAK1, ERK, and JNK and reduced AP-1 activation. Conclusions: These findings identify BTK as a key regulator of IL-1β–induced inflammatory and matrix-degradative responses via the TAK1–MAPK–AP-1 signaling axis. Targeting BTK may represent a potential therapeutic strategy for periodontitis.