WISP-3 Enhances Proinflammatory Cytokine IL-1β Production in Rheumatoid Arthritis Through the FAK, JNK and AP-1 Pathways

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and long-term disability. Interleukin-1β (IL-1β) is a key pro-inflammatory cytokine implicated in RA pathogenesis. Wnt1-inducible signaling pathway protein 3 (WISP-3) has been associated with joint homeostasis and RA development, but the molecular mechanisms by which WISP-3 regulates synovial inflammation remain poorly understood. Methods In this in vitro study, human RA synovial fibroblasts (RASFs) were treated with increasing concentrations of WISP-3 to evaluate IL-1β expression at both mRNA and protein levels. The involvement of focal adhesion kinase (FAK), c-Jun N-terminal kinase (JNK), and c-Jun signaling was investigated using pharmacological inhibitors and siRNA-mediated gene silencing. Protein phosphorylation and transcriptional activity were assessed to delineate the signaling cascade. Results WISP-3 significantly upregulated IL-1β expression in a dose-dependent manner. Mechanistic analyses demonstrated that WISP-3 activated FAK, which in turn induced phosphorylation of JNK and c-Jun. This signaling cascade enhanced transcriptional activity and promoted IL-1β production. Blockade of FAK, JNK, or c-Jun, either by selective inhibitors or siRNA-markedly attenuated WISP-3-induced IL-1β expression, confirming that the FAK/JNK/c-Jun axis plays a major role in WISP-3-induced IL-1β expression. Conclusion These in vitro findings indicate that WISP-3 acts as a pro-inflammatory mediator in RA by promoting IL-1β expression primarily through activation of the FAK/JNK/c-Jun pathway, with additional contributions from other signaling pathways.