The inflammatory cascade in the rheumatoid arthritis (RA) synovium is modulated by a variety of cytokine and chemokine networks; however, the roles of IL-26, in RA pathogenesis, are poorly defined. Here, we investigated the functional role of interleukin-26 (IL)-26 in osteoclastogenesis in RA. We analyzed levels of IL-20 receptor subunit A (IL-20RA), CD55, and receptor activator of nuclear factor kappaB (NF-κB) ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs) using confocal microscopy. Recombinant human IL-26-induced RANKL expression in RA-FLSs was examined using real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured with macrophage colony-stimulating factor (M-CSF) and IL-26, after which osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells. Additionally, osteoclastogenesis was evaluated by monocytes co-cultured with IL-26-prestimulated FLSs. The expression of IL-20RA in RA-FLSs was higher than that in osteoarthritis-FLSs. Additionally, in IL-26-pretreated RA-FLSs, the expression of IL-20RA (but not IL-10 receptor subunit B) and RANKL increased in a dose-dependent manner, with IL-26-induced RANKL expression reduced by IL-20RA knockdown. Moreover, IL-26-induced RANKL expression was significantly downregulated by inhibition of signal transducer and activator of transcription 1, mitogen-activated protein kinase, and NF-κB signaling. Furthermore, IL-26 promoted osteoclast differentiation from peripheral blood monocytes in the presence of low dose of RANKL, with IL-26 exerting an additive effect. Furthermore, co-culture of IL-26-pretreated RA-FLSs with peripheral blood monocytes also increased osteoclast differentiation in the absence of addition of RANKL. IL-26 regulated osteoclastogenesis in RA through increased RANKL expression in FLSs and direct stimulation of osteoclast differentiation. These results suggest the IL-26/IL-20RA/RANKL axis as a potential therapeutic target for addressing RA-related joint damage.

中文翻译：

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IL-26在类风湿关节炎中促进破骨细胞生成

类风湿关节炎（RA）滑膜中的炎症级联反应受到多种细胞因子和趋化因子网络的调节。但是，IL-26在RA发病机理中的作用尚不明确。在这里，我们调查了白介素-26（IL）-26在RA破骨细胞生成中的功能作用。我们使用共聚焦显微镜分析了RA成纤维样滑膜细胞（FLSs）中IL-20受体亚基A（IL-20RA），CD55和核因子κB（NF-κB）配体（RANKL）受体激活剂的水平。使用实时聚合酶链反应（PCR）和酶联免疫吸附测定（ELISA）检测了重组人IL-26诱导的RA-FLS中的RANKL表达。用巨噬细胞集落刺激因子（M-CSF）和IL-26培养人外周血单核细胞，然后通过计算抗酒石酸酸性磷酸酶阳性的多核细胞的数量来评估破骨细胞的形成。另外，通过与IL-26刺激的FLS共培养的单核细胞评估破骨细胞的形成。IL-20RA在RA-FLSs中的表达高于在骨关节炎-FLSs中的表达。此外，在经过IL-26预处理的RA-FLS中，IL-20RA（但不是IL-10受体亚基B）和RANKL的表达以剂量依赖性方式增加，而IL-26诱导的RANKL的表达则被IL-26降低。 20RA淘汰赛。此外，IL-26诱导的RANKL表达通过抑制信号转导子和转录激活子1，促有丝分裂原激活的蛋白激酶和NF-κB信号而显着下调。此外，在低剂量的RANKL存在下，IL-26促进破骨细胞从外周血单核细胞分化，而IL-26发挥累加作用。此外，在不添加RANKL的情况下，IL-26预处理的RA-FLS与外周血单核细胞的共培养也增加了破骨细胞的分化。IL-26通过增加FLSs中的RANKL表达和直接刺激破骨细胞分化来调节RA中的破骨细胞生成。这些结果表明，IL-26 / IL-20RA / RANKL轴是解决RA相关关节损伤的潜在治疗靶标。IL-26通过增加FLSs中的RANKL表达和直接刺激破骨细胞分化来调节RA中的破骨细胞生成。这些结果表明，IL-26 / IL-20RA / RANKL轴是解决RA相关关节损伤的潜在治疗靶标。IL-26通过增加FLSs中的RANKL表达和直接刺激破骨细胞分化来调节RA中的破骨细胞生成。这些结果表明，IL-26 / IL-20RA / RANKL轴是解决RA相关关节损伤的潜在治疗靶标。