Jang Jinah, Lim Dae-Seog, Choi Young-Eun, Jeong Yong, Yoo Seung-Ah, Kim Wan-Uk, Bae Yong-Soo
Department of Biological Science, Sungkyunkwan University, 300 Cheoncheon-dong, Suwon, Gyeonggi 440-746, Korea.
Arthritis Res Ther. 2006;8(6):R170. doi: 10.1186/ar2079.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of unclear etiology. This study was conducted to identify critical factors involved in the synovial hyperplasia in RA pathology. We applied cDNA microarray analysis to profile the gene expressions of RA fibroblast-like synoviocytes (FLSs) from patients with RA. We found that the MLN51 (metastatic lymph node 51) gene, identified in breast cancer, is remarkably upregulated in the hyperactive RA FLSs. However, growth-retarded RA FLSs passaged in vitro expressed small quantities of MLN51. MLN51 expression was significantly enhanced in the FLSs when the growth-retarded FLSs were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or synovial fluid (SF). Anti-GM-CSF neutralizing antibody blocked the MLN51 expression even though the FLSs were cultured in the presence of SF. In contrast, GM-CSF in SFs existed at a significant level in the patients with RA (n = 6), in comparison with the other inflammatory cytokines, IL-1beta and TNF-alpha. Most RA FLSs at passage 10 or more recovered from their growth retardation when cultured in the presence of SF. The SF-mediated growth recovery was markedly impaired by anti-GM-CSF antibody. Growth-retarded RA FLSs recovered their proliferative capacity after treatment with GM-CSF in a dose-dependent manner. However, MLN51 knock-down by siRNA completely blocked the GM-CSF/SF-mediated proliferation of RA FLSs. Taken together, our results imply that MLN51, induced by GM-CSF, is important in the proliferation of RA FLSs in the pathogenesis of RA.
类风湿关节炎（RA）是一种病因不明的炎症性自身免疫性疾病。本研究旨在确定类风湿关节炎病理中滑膜增生所涉及的关键因素。我们应用cDNA微阵列分析来描绘类风湿关节炎患者的类风湿成纤维样滑膜细胞（FLS）的基因表达。我们发现，在乳腺癌中鉴定出的MLN51（转移淋巴结51）基因在活跃的类风湿关节炎FLS中显著上调。然而，在体外传代的生长迟缓的类风湿关节炎FLS表达少量的MLN51。当生长迟缓的FLS用粒细胞-巨噬细胞集落刺激因子（GM-CSF）或滑液（SF）处理时，MLN51在FLS中的表达显著增强。抗GM-CSF中和抗体即使在FLS在SF存在下培养时也能阻断MLN51的表达。相比之下，与其他炎性细胞因子IL-1β和TNF-α相比，类风湿关节炎患者（n = 6）的滑液中GM-CSF水平显著升高。当在SF存在下培养时，大多数传代10次或更多次的类风湿关节炎FLS从生长迟缓中恢复。抗GM-CSF抗体显著损害了SF介导的生长恢复。生长迟缓的类风湿关节炎FLS在用GM-CSF处理后以剂量依赖的方式恢复了增殖能力。然而，通过siRNA敲低MLN51完全阻断了GM-CSF/SF介导的类风湿关节炎FLS的增殖。综上所述，我们的结果表明，由GM-CSF诱导的MLN51在类风湿关节炎发病机制中类风湿关节炎FLS的增殖中起重要作用。
