Interleukin-22 Promotes Osteoclastogenesis in Rheumatoid Arthritis Through Induction of RANKL in Human Synovial Fibroblasts
Interleukin-22 Promotes Osteoclastogenesis in Rheumatoid Arthritis Through Induction of RANKL in Human Synovial Fibroblasts
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DOI：
10.1002/art.33446
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发表时间：
2012-04-01
影响因子：
--
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
Objective.目的探讨白细胞介素-22（IL-22）在类风湿关节炎（RA）中对RANKL表达及破骨细胞生成的调节作用。采用酶联免疫吸附法检测RA患者血清和关节液中IL-22和RANKL的浓度。用重组人IL-22（rhIL-22）处理RA滑膜成纤维细胞，采用实时荧光定量PCR、Western blotting和细胞内免疫染色检测RANKL mRNA和蛋白的表达。将人单核细胞与IL-22预刺激的RA滑膜成纤维细胞和巨噬细胞集落刺激因子共培养，通过计数多核细胞（抗酒石酸酸性磷酸酶染色阳性的细胞）来评估破骨细胞生成。RA患者滑液中IL-22浓度高于骨关节炎（OA）患者。RA患者的血清IL-22浓度也高于OA患者和健康志愿者，这与类风湿因子和抗环瓜氨酸肽抗体的血清滴度相关。RA滑膜成纤维细胞经rhIL-22处理后，RANKL mRNA和蛋白表达呈剂量依赖性增加。IL-22诱导的RANKL表达通过抑制p38 MAPK/NF-κ B或JAK-2/STAT-3信号而显著下调。在IL-22刺激的RA滑膜成纤维细胞与人单核细胞共培养中，在不存在外源性RANKL的情况下，单核细胞分化为破骨细胞，但在p38 MAPK/NF-κ B或JAK-2/STAT-3信号转导被抑制后，这种破骨细胞生成减少。这些结果表明，IL-22上调RA滑膜成纤维细胞中的RANKL表达并诱导破骨细胞生成。这些作用由p38 MAPK/NF-κ B和JAK-2/STAT-3信号通路介导。
Objective. To examine the regulatory role of interleukin-22 (IL-22) in the expression of RANKL and induction of osteoclastogenesis in rheumatoid arthritis (RA).Methods. Concentrations of IL-22 and RANKL in the serum and synovial fluid of RA patients were measured using enzyme-linked immunosorbent assay. RA synovial fibroblasts were treated with recombinant human IL-22 (rhIL-22), and the expression of RANKL messenger RNA (mRNA) and protein was measured using real-time polymerase chain reaction, Western blotting, and intracellular immunostaining. Human monocytes were cocultured with IL-22-prestimulated RA synovial fibroblasts and macrophage colony-stimulating factor, and osteoclastogenesis was assessed by counting the multinucleated cells (those staining positive for tartrate-resistant acid phosphatase).Results. The IL-22 concentration in the synovial fluid was higher in RA patients than in patients with osteoarthritis (OA). The serum IL-22 concentration was also higher in RA patients than in OA patients and healthy volunteers, and this correlated with serum titers of rheumatoid factor and anti-cyclic citrullinated peptide antibodies. In RA synovial fibroblasts treated with rhIL-22, the expression of RANKL mRNA and protein was increased in a dose-dependent manner. IL-22-induced RANKL expression was down-regulated significantly by the inhibition of p38 MAPK/NF-kappa B or JAK-2/STAT-3 signaling. In human monocytes cocultured with IL-22-prestimulated RA synovial fibroblasts in the absence of exogenous RANKL, the monocytes differentiated into osteoclasts, but this osteoclastogenesis decreased after p38 MAPK/NF-kappa B or JAK-2/STAT-3 signaling was inhibited.Conclusion. These results show that IL-22 up-regulates RANKL expression in RA synovial fibroblasts and induces osteoclastogenesis. These effects are mediated by the p38 MAPK/NF-kappa B and JAK-2/STAT-3 signaling pathways.