Purpose. Interleukin-1α (IL-1α) is a potent cytokine that plays a role in inflammatory arthritis and bone loss. Decoy receptor 3 (DCR3) is an immune modulator of monocytes and macrophages. The aim of this study was to investigate the mechanism of DCR3 in IL-1α-induced osteoclastogenesis. Methods. We treated murine macrophages with DCR3 during receptor activator of nuclear factor kappa Β ligand- (RANKL-) plus IL-1α-induced osteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed using a pit formation assay. The mechanisms of inhibition were studied by biochemical analyses, including RT-PCR, immunofluorescent staining, flow cytometry, an apoptosis assay, immunoblotting, and ELISA. Results. DCR3 suppresses IL-1α-induced osteoclastogenesis in both primary murine bone marrow-derived macrophages (BMM) and RAW264.7 cells as it inhibits bone resorption. DCR3 induces RANKL-treated osteoclast precursor cells to express IL-1α, secretory IL-1ra (sIL-1ra), intracellular IL-1ra (icIL-1ra), reactive oxygen species (ROS), and Fas ligand and to activate IL-1α-induced interleukin-1 receptor-associated kinase 4 (IRAK4). The suppression of DCR3 during RANKL- or IL-1α-induced osteoclastogenesis may be due to the abundant secretion of IL-1ra, accumulation of ROS, and expression of Fas ligand in apoptotic osteoclast precursor cells. Conclusions. We concluded that there is an inhibitory effect of DCR3 on osteoclastogenesis via ROS accumulation and ROS-induced Fas ligand, IL-1α, and IL-1ra expression. Our results suggested that the upregulation of DCR3 in preosteoclasts might be a therapeutic target in inflammatory IL-1α-induced bone resorption.

中文翻译：

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Decoy Receptor 3 通过活性氧诱导的 Fas 配体表达和 IL-1α/IL-1 受体拮抗剂途径促进破骨前细胞死亡。

目的。白细胞介素 1 α (IL-1 α ) 是一种有效的细胞因子，在炎症性关节炎和骨质流失中发挥作用。诱饵受体 3 (DCR3) 是单核细胞和巨噬细胞的免疫调节剂。本研究的目的是研究 DCR3 在 IL-1 α诱导的破骨细胞生成中的作用机制。方法。我们在核因子 kappa β 配体-(RANKL-) 加 IL-1 α的受体激活剂期间用 DCR3 处理鼠巨噬细胞-诱导破骨细胞生成，通过抗酒石酸酸性磷酸酶 (TRAP) 染色监测破骨细胞的形成。使用凹坑形成测定法评估破骨细胞活性。通过生化分析研究抑制机制，包括RT-PCR、免疫荧光染色、流式细胞术、细胞凋亡测定、免疫印迹和ELISA。结果。DCR3在原代鼠骨髓衍生巨噬细胞 (BMM) 和 RAW264.7 细胞中抑制 IL-1 α诱导的破骨细胞生成，因为它抑制骨吸收。DCR3 诱导 RANKL 处理的破骨细胞前体细胞表达 IL- 1α、分泌型 IL-1ra (sIL-1ra)、细胞内 IL-1ra (icIL-1ra)、活性氧 (ROS) 和 Fas 配体并激活 IL- 1α _-诱导的白细胞介素 1 受体相关激酶 4 (IRAK4)。在 RANKL 或 IL-1 α诱导的破骨细胞生成过程中 DCR3 的抑制可能是由于 IL-1ra 的大量分泌、ROS 的积累和凋亡破骨细胞前体细胞中 Fas 配体的表达。结论。我们得出结论，DCR3 通过 ROS 积累和 ROS 诱导的 Fas 配体、IL-1 α和 IL-1ra 表达对破骨细胞生成具有抑制作用。我们的结果表明，前破骨细胞中 DCR3 的上调可能是炎症性 IL-1 α诱导的骨吸收的治疗靶点。