Release of endogenous anti-inflammatory complement regulators FHL-1 and factor H protects synovial fibroblasts during rheumatoid arthritis
Release of endogenous anti-inflammatory complement regulators FHL-1 and factor H protects synovial fibroblasts during rheumatoid arthritis
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DOI：
10.1046/j.1365-2249.2003.02173.x
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发表时间：
2003-06-01
影响因子：
4.6
通讯作者：
Zipfel, PF
中科院分区：
文献类型：
--
作者：
Friese, MA;Manuelian, T;Zipfel, PF
类风湿关节炎是一种病因不明的慢性炎症性疾病，主要累及滑膜关节的细胞和组织。在这里，我们证明了两个重要的补体调节因子FHL-1和H因子在类风湿关节炎中起到保护性抗炎作用。MRNA和蛋白质水平的表达分析表明，来自类风湿关节炎患者的滑膜成纤维细胞在体外表达和分泌这两种调节因子。同样，这两种调节因子在患病的滑膜组织中也是在体内合成的，尤其是滑膜衬里细胞表达高水平的FHL-1。这些调节剂在类风湿性关节炎中的抗炎作用在干扰素-γ和地塞米松的诱导下得到了强调，而促炎细胞因子肿瘤坏死因子-α则没有作用。用不同的FHL-1/FFH启动子-荧光素酶报告结构瞬时转染不同来源的细胞的实验表明，独立的细胞和组织特异性启动子调控这两种调控因子的转录。诱导表达，特别是FHL-1的诱导表达具有生理后果。通过直接与表面结合，释放的蛋白质保护细胞免受炎症损伤和补体介导的细胞溶解。这项研究显示了两种重要的补体调节因子FHL-1和因子H在类风湿关节炎中的新的保护和抗炎作用，并暗示了这两种蛋白的疾病控制作用。
Rheumatoid arthritis is a chronic inflammatory disease of unknown aetiology predominantly affecting cells and tissues of synovial joints. Here we show that the two important complement regulators FHL-1 and factor H play a protective anti-inflammatory role in rheumatoid arthritis. Expression analyses at the mRNA- and protein level show in vitro expression and secretion of both regulators by synovial fibroblasts derived from patients with rheumatoid arthritis. Similarly the two regulators are synthesized in vivo in diseased synovial tissue, and in particular synovial lining cells express high levels of FHL-1. The anti-inflammatory role of these regulators in rheumatoid arthritis is highlighted by their induction with IFN-gamma and dexamethasone, whilst the pro-inflammatory cytokine TNF-alpha had no effect. Transient transfection experiments with various FHL-1/factor H promoter-luciferase reporter constructs into cells of distinct origin show independent cell and tissue specific promoter regulated transcription of these two regulators. The inducible expression, specifically of FHL-1 has physiological consequences. By binding directly to surfaces the released proteins protect cells from inflammatory damage and complement-mediated cell lysis. This study shows a novel protective and anti-inflammatory role of the two important complement regulators FHL-1 and factor H in rheumatoid arthritis and suggests a disease controlling role of the two proteins.