北京大学最新成果登本领域权威期刊

　　生物通报道：来自北京大学人民医院风湿免疫科，美国天普大学等处的研究人员发表了题为“Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis”的文章，指出低氧和低氧诱导因子（HIF）-1α可激活天然免疫反应，诱发类风湿关节炎（RA）的发生，这一新的发病机制的发现可以作为生物治疗的新靶点，有望成为类风湿关节炎领域的突破口。

这一研究成果公布在风湿免疫专业领域权威期刊Ann Rheum Dis（影响因子9.111）上，这一杂志是国际同行评审期刊，致力于促进科技交流和教育的最高标准。它涵盖了风湿病的各个方面，其中包括肌肉骨骼，关节疾病，结缔组织疾病的频谱。

类风湿性关节炎是一种自身免疫性疾病，这种疾病会引起肢体严重畸形，关节滑膜炎及浆膜、心肺、皮肤、眼、血管等结缔组织广泛性炎症，类风湿性关节炎发病率高，是一个世界范围内的疾病，分布于所有的种族和民族。类风湿性关节炎至今尚无特效疗法，仍停留于对炎症及后遗症的治疗。近年来对于类风湿关节炎的治疗提出了许多的新方法，如生物制剂治疗、造血干细胞移植、基因治疗等，但仍没有一种方法能治愈这一疾病。随着病情的逐渐发展，类风湿关节炎最终可导致关节畸形，功能丧失。

在这篇文章中，研究人员发现，在低氧条件下，细菌、病毒等天然感染可以刺激类风湿关节炎滑膜成纤维细胞（RASF）分泌更多的炎性细胞因子白细胞介素（IL）-6、IL-8以及肿瘤坏死因子（TNF）-α等。正反两方面的研究证实，低氧诱导因子HIF-1α在这一过程中发挥着枢纽作用。进一步的功能研究揭示，RASF中HIF-1α的表达水平越高，其促进T细胞介导的炎症反应的能力越强，相应的类风湿关节炎病情也越严重。

这项研究在世界上首次证实了低氧及HIF-1α与toll样受体（TLR）通路两种作用方式在类风湿性关节炎发病过程中具有协同作用，研究提示，“双管齐下”，同时应用阻断两个通路的药物将取得更好的治疗效果，改善类风湿关节炎预后。

针对已取得的研究成果，栗占国教授课题组将进行临床前药物研究，以验证联合治疗的有效性。此外，课题组还将继续深入探讨HIF-1α在类风湿关节炎发病中的作用，以进一步诠释类风湿关节炎的发病机制。

原文摘要：

Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis

Objectives Hyperplasia of synovial fibroblasts, infiltration with lymphocytes and tissue hypoxia are major characteristics of rheumatoid arthritis (RA). Extensive data support a key role for toll-like receptors (TLRs) in RA. Little is known regarding the impact of hypoxia on TLR-induced inflammation in RA. The aim of this study was to reveal the effects of hypoxia and its regulator, hypoxia-inducible factor-1α (HIF-1α), on the inflammatory response of RA synovial fibroblasts (RASF) to TLR ligands.

Methods Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand peptidoglycan, TLR4 ligand LPS and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on TLR-induced inflammatory mediators were determined by RT-PCR, qPCR and ELISA. Overexpression of HIF-1α as well as knocking-down its expression was used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry analysis of T helper (Th)1/Th17 cells, and IFN-γ/IL-17 production by ELISA after RASF/T cell coculture.

Results Hypoxia potentiated the expression of inflammatory cytokines, metalloproteinases and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from viruses or apoptotic cells. HIF-1α played a fundamental role in this synergy. Moreover, HIF-1α overexpression enhanced RASF-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory IFN-γ and IL-17 production.

Conclusions Our findings suggest that hypoxia and HIF-1α may function in conjunction with TLR-stimulated innate immune responses to drive inflammation in RA. This pathway may serve as a therapeutic target for the disease.