WISP-3 enhances proinflammatory cytokine IL-1β production in rheumatoid arthritis through the FAK, JNK and AP-1 pathways

  • Cell Immunol. 2026 Jul:425:105103. doi: 10.1016/j.cellimm.2026.105103.
Sheng-Mou Hou  1 ,  Guo-Shou Wang  2 ,  Jeng-Hung Guo  3 ,  Chun-Lin Liu  3 ,  Chao-Ju Chen  4 ,  Chih-Hsin Tang  5 ,  Chih-Yang Lin  6
Affiliations
  • 1. Department of Research, Taiwan Blood Services Foundation, Taipei 100231, Taiwan, ROC; The Director's Office, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan, ROC.
  • 2. Department of Medicine, MacKay Medical College, New Taipei City 23245, Taiwan, ROC; Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei 104217, Taiwan, ROC.
  • 3. Department of Neurosurgery, China Medical University Hospital, Taichung 40402, Taiwan, ROC.
  • 4. Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan, ROC.
  • 5. Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413305, Taiwan, ROC; Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan, ROC. Electronic address: [email protected].
  • 6. Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan, ROC; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan, ROC. Electronic address: [email protected].
PMID: 41955703 DOI: 10.1016/j.cellimm.2026.105103
Abstract

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.

Keywords
IL-1β; Rheumatoid arthritis; Signal transduction; WISP-3.
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