糖皮质激素和肿瘤坏死因子抑制剂通过上调淋巴细胞激活基因-3发挥的滑膜炎症新抑制途径：一项体外研究
A novel inhibitory pathway of synovial inflammation exerted by glucocorticoids and tumour necrosis factor inhibitors via lymphocyte activation gene-3 up-regulation: an ex vivo study.
作者信息
Gertel Smadar, Polachek Ari, Eviatar Tali, Elkayam Ori, Furer Victoria
机构信息
Department of Rheumatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
出版信息
Rheumatology (Oxford). 2025 Apr 1;64(4):1689-1697. doi: 10.1093/rheumatology/keae389.
OBJECTIVE
To investigate the impact of glucocorticoids (GCs) and anti-rheumatic drugs on lymphocyte activation gene-3 (LAG-3) and on programmed cell death-1 (PD-1) expression by synovial and peripheral cells ex vivo.
METHODS
Synovial fluid mononuclear cells (SFMCs) from psoriatic arthritis (PsA, n = 26) and rheumatoid arthritis (RA, n = 13) patients, synovial fluid cells (SFCs) from osteoarthritis (OA, n = 5) patients and peripheral blood mononuclear cells (PBMCs) of healthy donors (n = 14) were co-cultured with GCs, glucocorticoid receptor antagonist RU486, methotrexate (MTX) and biologics. LAG-3 and PD-1 expression on immune subsets were analysed by flow cytometry.
RESULTS
GCs in PsA inhibited SFMC growth vs medium [2.3 (0.4) × 105vs 5.3 (0.7) × 105, respectively, P < 0.01] and markedly up-regulated CD14+LAG-3+ cells [11.7 (2.4)% vs 0.8 (0.3)%, P < 0.0001, respectively], but not CD3+LAG-3+ and CD14+PD-1+ cells. MTX had no effect on CD14+LAG-3+ cells [0.7 (0.3)%]. The TNF inhibitors infliximab (IFX) and etanercept, but not IL-12/23 inhibitor, up-regulated CD14+LAG-3+ cells vs medium [2.0 (0.6)% and 1.6 (0.4)% vs 0.5 (0.1)%, P < 0.03, respectively]. SFMC growth inhibition by GC in both PsA and RA correlated with CD14+LAG-3+ cell up-regulation (r = 0.53, P = 0.03). RU486 inhibited GC-induced CD14+LAG-3+ cells up-regulation in a dose-dependent manner compared with GC alone [5 µM 5.3 (1.2)% and 50 µM 1.3 (0.5)% vs 7.0 (1.4)%, P < 0.003], but had no significant effect on CD14+LAG-3+ cells co-cultured with IFX. GCs in healthy donors' PBMCs up-regulated the immune subsets CD3+LAG-3+, CD14+LAG-3+ and CD14+PD-1+ cells.
CONCLUSION
This study proposes a novel regulatory mechanism of GCs and of TNF inhibitors mediated by LAG-3 up-regulation in synovial cells and PBMCs. LAG-3 modulation may be a promising target for development of novel therapies for inflammatory arthritis.
目的
研究糖皮质激素（GCs）和抗风湿药物对离体滑膜细胞和外周细胞中淋巴细胞激活基因-3（LAG-3）及程序性细胞死亡蛋白-1（PD-1）表达的影响。
方法
将银屑病关节炎（PsA，n = 26）和类风湿关节炎（RA，n = 13）患者的滑膜液单核细胞（SFMCs）、骨关节炎（OA，n = 5）患者的滑膜液细胞（SFCs）以及健康供者（n = 14）的外周血单核细胞（PBMCs）与GCs、糖皮质激素受体拮抗剂RU486、甲氨蝶呤（MTX）和生物制剂共同培养。通过流式细胞术分析免疫亚群上LAG-3和PD-1的表达。
结果
PsA患者的GCs与培养基相比抑制了SFMC生长[分别为2.3（0.4）×10⁵ 对5.3（0.7）×10⁵，P < 0.01]，并显著上调了CD14⁺LAG-3⁺细胞[分别为11.7（2.4）% 对0.8（0.3）%，P < 0.0001]，但对CD3⁺LAG-3⁺和CD14⁺PD-1⁺细胞无影响。MTX对CD14⁺LAG-3⁺细胞无影响[0.7（0.3）%]。肿瘤坏死因子抑制剂英夫利昔单抗（IFX）和依那西普上调了CD14⁺LAG-3⁺细胞，而白细胞介素-12/23抑制剂则未上调，与培养基相比[分别为2.0（0.6）%和1.6（0.4）% 对0.5（0.1）%，P < 0.03]。PsA和RA中GC对SFMC生长的抑制与CD14⁺LAG-3⁺细胞上调相关（r = 0.53，P = 0.03）。与单独使用GC相比，RU486以剂量依赖方式抑制GC诱导的CD14⁺LAG-3⁺细胞上调[5 μM时为5.3（1.2）%，50 μM时为1.3（0.5）% 对7.0（1.4）%，P < 0.003]，但对与IFX共同培养的CD14⁺LAG-3⁺细胞无显著影响。健康供者PBMCs中的GCs上调了免疫亚群CD3⁺LAG-3⁺、CD14⁺LAG-3⁺和CD14⁺PD-1⁺细胞。
结论
本研究提出了一种由滑膜细胞和PBMCs中LAG-3上调介导的GCs和肿瘤坏死因子抑制剂的新型调节机制。LAG-3调节可能是炎性关节炎新型疗法开发的一个有前景的靶点。
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