Hypoxia-inducible factor-1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis
Hypoxia-inducible factor-1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis
复制标题
类风湿性关节炎中缺氧诱导因子 1 α 使滑膜成纤维细胞与 T 细胞和 B 细胞持续相互作用
DOI：
10.1002/eji.201545784
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发表时间：
2016-03-01
影响因子：
5.4
通讯作者：
Li, Zhanguo
中科院分区：
文献类型：
--
作者：
Hu, Fanlei;Liu, Hongjiang;Li, Zhanguo
类风湿关节炎(RA)的主要特征是滑膜成纤维细胞增生、T细胞过度活化、B细胞过度活化以及这些细胞之间的自持性相互作用。RA患者炎症关节呈低氧状态，RA滑膜成纤维细胞(RASF)低氧诱导因子-1α(HIF-1α)表达上调。目前尚不清楚HIF-1α是否调节RASF与T细胞和B细胞之间的相互作用。我们在此报道，HIF-1α促进RASF中炎性细胞因子IL-6、IL-8、TNF-α和IL-1β以及细胞-细胞接触介质IL-15、血管细胞黏附分子(VCAM)-1、血栓反应蛋白(TSP)-1和基质细胞衍生因子(SDF)-1的表达。此外，HIF-1α维持RASF介导的炎性Th1和Th17细胞的扩张，同时不同程度地抑制调节性B10和先天B细胞，导致干扰素-γ、IL-17和免疫球蛋白G的产生增加，保护性天然IgM分泌减少。我们的发现表明，HIF-1α使RASF与T细胞和B细胞之间的相互作用持续存在，从而诱导炎性细胞因子和自身抗体的产生，从而加剧了RA的严重程度。靶向HIF-1α可能为克服这种顽固性疾病提供新的治疗策略。
Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1 alpha regulates interactions between RASFs and T cells and B cells. We report here that HIF-1 alpha promotes the expression of inflammatory cytokines IL-6, IL-8, TNF-alpha, and IL-1 beta, and cell-cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1 alpha perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-gamma, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1 alpha perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1 alpha may provide new therapeutic strategies for overcoming this persistent disease.