Cytokine · 2026
IL-6 trans-signaling activates the TGF-β pathway via soluble factors in difficult-to-treat rheumatoid arthritis joint fluid.
СтатьяНазвание и аннотация: Перевод в очереди
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Bei-Bei Yang, Ji-Zan Liu, Hong-Bing Rui, Juan Xue, Hua Xiao
Аннотация
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.
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.