CD14-positive monocytes from patients with rheumatoid arthritis (RA) are more resistant to apoptosis, which promotes their persistence at the inflammatory site and thereby contributes crucially to immunopathology. We sought to elucidate one mechanism underlying this unique pathogenesis: resistance to apoptosis and the potential involvement of miR-29b in this process. CD14-positive peripheral blood monocytes (PBMs) from RA patients were observed to be resistant to spontaneous apoptosis compared to PBMs from healthy volunteers. Intriguingly, expression of miR-29b was significantly upregulated in PBMs from RA patients than those from healthy volunteers, and this upregulation was correlated with RA disease activity. Functionally, forced expression of the exogenous miR-29b in CD14-positive Ctrl PBMs conferred resistance to spontaneous apoptosis and Fas-induced death, thereafter enhancing the production of major proinflammatory cytokines in there cells. Following identification of the potential miR-29b target transcripts using bioinformatic algorithms, we showed that miR-29b could directly bind to the 3'-UTR of the high-mobility group box-containing protein 1 (HBP1) and inhibited its transcription in PBMs. Importantly, stable expression of the exogenous HBP1 in differentiated THP-1 monocytes effectively abolished miR-29b-elicited resistance to Fas-induced apoptosis. Finally, among patients with RA and good clinical responses to immunotherapy, expression levels of miR-29b were significantly compromised in those treated with infliximab (a TNF-α inhibitor) but not in those treated with tocilizumab (a humanized mAb against the IL-6 receptor), pointing to a potential association between miR-29b activation and TNF-α induction. The available data collectively suggest that TNF-α-elicited miR-29b potentiates resistance to apoptosis in PBMs from RA patients via inhibition of HBP1 signaling, and testing patients for miR-29b/HBP1 expression ratios may provide more accurate prognostic information and could influence the recommended course of immunotherapy.

中文翻译：

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TNF-α诱导的miR-29b增强了对类风湿关节炎患者外周血单核细胞凋亡的抗性。

类风湿性关节炎（RA）患者的CD14阳性单核细胞对细胞凋亡具有更高的抵抗力，从而促进其在炎症部位的持久性，从而对免疫病理学至关重要。我们试图阐明这种独特发病机理的一种机制：对细胞凋亡的抗性以及miR-29b在此过程中的潜在参与。与健康志愿者的PBM相比，观察到RA患者的CD14阳性外周血单核细胞（PBM）对自发凋亡具有抗性。有趣的是，与健康志愿者相比，RA患者的PBM中miR-29b的表达显着上调，并且这种上调与RA疾病活动相关。在功能上 CD14阳性Ctrl PBM中外源性miR-29b的强制表达赋予了对自发凋亡和Fas诱导的死亡的抵抗力，此后增强了那里细胞中主要促炎细胞因子的产生。使用生物信息学算法鉴定潜在的miR-29b靶转录本后，我们显示miR-29b可以直接结合至高迁移率基盒蛋白1（HBP1）的3'-UTR，并抑制其在PBM中的转录。重要的是，外源HBP1在分化的THP-1单核细胞中的稳定表达有效地消除了miR-29b引起的对Fas诱导的细胞凋亡的抵抗。最后，在RA且对免疫疗法的临床反应良好的患者中，在用英夫利昔单抗（一种TNF-α抑制剂）治疗的患者中，miR-29b的表达水平显着降低，但在用托珠单抗（一种针对IL-6受体的人源化单克隆抗体）治疗的患者中，miR-29b的表达水平却受到显着影响，这表明miR-29b激活之间可能存在关联和TNF-α诱导。现有数据共同表明，TNF-α诱导的miR-29b通过抑制HBP1信号传导增强了RA患者PBM的凋亡抗性，测试患者的miR-29b / HBP1表达比可能提供更准确的预后信息，并可能影响预后。推荐的免疫疗法疗程。