Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
PLoS One. 2013 Aug 15;8(8):e72650. doi: 10.1371/journal.pone.0072650. eCollection 2013.
Hyperplasia of synovial fibroblasts, infiltration with inflammatory cytokines, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Interleukin 33 (IL-33) is a newly identified inflammatory cytokine exacerbating the disease severity of RA. Hypoxia-inducible factor-1α (HIF-1α) showed increased expression in RA synovium and could regulate a number of inflammatory cytokine productions. Nevertheless, its correlation with IL-33 remains largely unknown. Here, we showed that elevated levels of IL-33 were demonstrated in RA patient synovial fluids, with upregulated expression of HIF-1α and IL-33 in the synovial fibroblasts. Knocking down HIF-1α compromised IL-33 expression in rheumatoid arthritis synovial fibroblasts (RASF), while enforcing HIF-1α expression in RASF substantially upregulated IL-33 levels. HIF-1α promoted the activation of the signalling pathways controlling IL-33 production, particularly the p38 and ERK pathways. Moreover, we showed for the first time that IL-33 in turn could induce more HIF-1α expression in RASF, thus forming a HIF-1α/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA. Targeting this pathological pathway and HIF-1α may provide new therapeutic strategies for overcoming the persistent and chronic inflammatory disease.
滑膜成纤维细胞增生、炎症细胞因子浸润和组织缺氧是类风湿关节炎（RA）的主要特征。白细胞介素 33（IL-33）是一种新发现的炎症细胞因子，可加重 RA 的疾病严重程度。缺氧诱导因子-1α（HIF-1α）在 RA 滑膜中表达增加，可调节多种炎症细胞因子的产生。然而，其与 IL-33 的相关性尚不清楚。在这里，我们表明 RA 患者滑膜液中 IL-33 水平升高，滑膜成纤维细胞中 HIF-1α 和 IL-33 的表达上调。敲低 HIF-1α 可降低类风湿关节炎滑膜成纤维细胞（RASF）中 IL-33 的表达，而增强 HIF-1α 在 RASF 中的表达则可显著上调 IL-33 水平。HIF-1α 促进了控制 IL-33 产生的信号通路的激活，特别是 p38 和 ERK 通路。此外，我们首次表明，IL-33 反过来又可在 RASF 中诱导更多的 HIF-1α 表达，从而形成一个 HIF-1α/IL-33 调节回路，使 RA 中的炎症过程持续存在和慢性化。针对这条病理途径和 HIF-1α 可能为克服持续性和慢性炎症性疾病提供新的治疗策略。
