Endoplasmic reticulum (ER) stress associated proteins contribute to the pathogenesis of rheumatoid arthritis (RA) through affecting synoviocyte proliferation and proinflammatory cytokine production. The role of DERL3, an ER-associated degradation component, in joint inflammation of RA was explored. Synovial tissues from RA and osteoarthritis (OA) patients were collected, and in RA synovial tissue, DERL3 showed up-regulation and significantly positive correlation with the expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-1. Immunofluorescence result suggested DERL3 was located in fibroblast-like synoviocytes (FLS). Among different inflammatory stimuli, DERL3 could be up-regulated by TNF-α stimulation in FLS. Under TNF-α stimulation, knocking down DERL3, the expression of IL-6, IL-8, MMP-1, MMP-13 was reduced and the activation of nuclear factor kappa B (NF-κB) signaling pathway was inhibited. In pristane-induced arthritis (PIA) rat model, Derl3 was up-regulated in synovial tissue and disease was attenuated after intraarticular injection of siDerl3. Overall, we conclude that TNF-α inducing DERL3 expression promotes the inflammation of FLS through activation of NF-κB signaling pathway, suggesting DERL3 plays important roles in the pathogenesis of RA and is a promising therapeutic target.

内质网（ER）应激相关蛋白通过影响滑膜细胞增殖和促炎细胞因子的产生，促进了类风湿关节炎（RA）的发病。探索了与ER相关的降解成分DERL3在RA关节炎症中的作用。收集RA和骨关节炎（OA）患者的滑膜组织，在RA滑膜组织中，DERL3呈上调并与肿瘤坏死因子α（TNF-α），白介素（IL）-6和基质的表达显着正相关金属蛋白酶（MMP）-1。免疫荧光结果提示DERL3位于成纤维样滑膜细胞（FLS）中。在不同的炎症刺激中，可通过FLS中的TNF-α刺激来上调DERL3。在TNF-α刺激下，敲低DERL3，降低IL-6，IL-8，MMP-1，MMP-13的表达，并抑制核因子κB（NF-κB）信号通路的激活。在p烷诱发的关节炎（PIA）大鼠模型中，关节内注射si Derl3后，滑膜组织中的Derl3上调，疾病减轻。总的来说，我们得出结论，TNF-α诱导DERL3 表达通过激活NF-κB信号通路促进FLS的炎症，提示DERL3在RA的发病机理中起着重要的作用，是有希望的治疗靶点。