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Updated: Jan 13, 2026

An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
IL-6 trans-signaling activates the TGF-β pathway via soluble factors in difficult-to-treat rheumatoid arthritis joint
Yang Bei-Bei1, Liu Ji-Zan2, Rui Hong-Bing2
1Department of Dermatology, Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center), College of Clinical Medicine for Obstetrics&Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350003, China.
Objective:
To explore the impact of joint fluid (JF) from difficult-to-treat (D2T)rheumatoid arthritis (RA) patients on joint inflammation.
Methods:
We compared the clinical characteristics of D2T RA and non-D2T RA patients. Joint fluid samples from patients with various forms of chronic arthritis were analyzed. The activation of IL-6/STAT3 and TGF-β/SMAD3 pathways in normal Fibroblast-like synoviocytes (FLS) after exposure to D2T RA joint fluid was also evaluated, along with the effects of pathway inhibitors on cell proliferation, apoptosis, invasion, and migration.
Results:
D2T RA joint fluid showed elevated levels of IL-6 and TGF-β1 compared to non-D2T RA, osteoarthritis, and ankylosing spondylitis samples. The IL-6/STAT3 pathway was directly activated in normal FLS upon exposure to D2T RA joint fluid, while the TGF-β/SMAD3 pathway was indirectly activated through IL-6 trans-signaling, resulting in increased proliferation, migration, invasion, and anti-apoptotic properties of FLS. The use of SMAD3 Inhibitory Selective 3 (SIS3) to block the TGF-β/SMAD3 pathway partially mitigated the effects of D2T RA joint fluid. Tocilizumab and the soluble glycoprotein 130 Fc fusion protein (sgp130Fc) successfully inhibited IL-6-associated pSMAD3 activation, highlighting a mediating role of IL-6.
Conclusion:
The joint fluid milieu may contribute to persistent synovial activation in D2T RA, and highlights IL-6 trans-signaling as a potential therapeutic target in this context. In addition, timely aspiration of joint fluid from patients with D2T RA may help modulate the local inflammatory microenvironment and could represent a supportive strategy in disease management.
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