Th17 Cytokines Regulate Osteoclastogenesis in Rheumatoid Arthritis
Th17 Cytokines Regulate Osteoclastogenesis in Rheumatoid Arthritis
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DOI：
10.1016/j.ajpath.2015.07.017
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发表时间：
2015-11-01
影响因子：
6
通讯作者：
Lee, Sang-Heon
中科院分区：
文献类型：
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作者：
Kim, Kyoung-Woon;Kim, Hae-Rim;Lee, Sang-Heon
本研究确定了17型辅助性T细胞（Th 17）细胞因子对类风湿关节炎（RA）破骨细胞生成的影响。采用免疫组化和酶联免疫吸附试验检测RA患者滑膜组织、成纤维细胞样滑膜细胞（FLS）和滑液中IL-17和NE-κ B受体激活因子配体（RANKL）的表达。通过实时PCR、荧光素酶活性测定和Western印迹分析研究了RA FLS中Th 17细胞因子诱导的RANKL表达。人外周血单核细胞与巨噬细胞集落刺激因子和Th 17细胞因子一起培养，之后通过计数抗酒石酸酸性磷酸酶阳性多核细胞的数量来评估破骨细胞生成。在单核细胞与IL-17预刺激的FLS共培养后，还评价了破骨细胞生成。RA患者关节液中RANKL与IL-17水平呈显著相关。IL-17、IL-21和IL-22增加RA FLS中Rankl mRNA的表达，并且通过抑制Act 1、肿瘤坏死因子受体相关因子6、NE-κ B和激活蛋白-1来降低IL-17诱导的RANKL表达。Th 17细胞因子和IL-17预刺激的FLS在不存在外源性RANKL的情况下诱导单核细胞的破骨细胞生成。抑制肿瘤坏死因子-cc可降低骨诱导作用。Th 17细胞因子对RA中的破骨细胞生成具有双重作用：直接诱导单核细胞的破骨细胞生成和上调RA FLS中RANKL的产生。这种Th 17细胞因子/RANKL轴可能是RA骨破坏的潜在治疗靶点。
This study determined the effect of type 17 helper T-cell (Th17) cytokines on osteoclastogenesis in rheumatoid arthritis (RA). The expression of IL-17 and receptor activator of NE-kappa B ligand (RANKL) was determined in synovial tissue, fibroblast-like synoviocytes (FLSs), and synovial fluids of RA patients using immunostaining and enzyme-linked immunosorbent assay. Th17 cytokine induced RANKL expression was studied in RA FLS by using real-time PCR, luciferase activity assays, and Western blot analysis. Human peripheral blood monocytes were cultured with macrophage colony-stimulating factor and Th17 cytokines, after which osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase positive multinucleated cells. Osteoclastogenesis was also evaluated after monocytes were co-cultured with IL-17-prestimulated FLS. There was significant correlation between RANKL and IL-17 levels in RA synovial fluid. IL-17, IL-21, and IL-22 increased the expression of Rankl mRNA in RA FLS, and the IL-17 induced RANKL expression decreased by the inhibition of Act1, tumor necrosis factor receptor associated factor 6, NE-kappa B, and activator protein-1. Th17 cytokines and IL-17 prestimulated FLS induced osteoclastogenesis from monocytes in the absence of exogenous RANKL. The osteoclastic effect was reduced by inhibition of tumor necrosis factor-cc. Th17 cytokines have a dual effect on osteoclastogenesis in RA: direct induction of osteoclastogenesis from monocytes and up-regulation of RANKL production in RA FLS. This Th17 cytokine/RANKL axis could be a potential therapeutic target for bone destruction in RA.