The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the infiltration of immune cells into the joints of F759 mice. The result is a disease that resembles human rheumatoid arthritis. However, the kinetics and regulatory mechanisms of how augmented transcriptional activation by STAT3 and NF-κB leads to F759 arthritis is unknown. We here show that the STAT3-NF-κB complex is present in the cytoplasm and nucleus and accumulates around NF-κB binding sites of the IL-6 promoter region and established a computer model that shows IL-6 and IL-17 (interleukin 17) signaling promotes the formation of the STAT3-NF-κB complex followed by its binding on promoter regions of NF-κB target genes to accelerate inflammatory responses, including the production of IL-6, epiregulin, and C-C motif chemokine ligand 2 (CCL2), phenotypes consistent with in vitro experiments. The binding also promoted cell growth in the synovium and the recruitment of T helper 17 (Th17) cells and macrophages in the joints. Anti-IL-6 blocking antibody treatment inhibited inflammatory responses even at the late phase, but anti-IL-17 and anti-TNFα antibodies did not. However, anti-IL-17 antibody at the early phase showed inhibitory effects, suggesting that the IL-6 amplifier is dependent on IL-6 and IL-17 stimulation at the early phase, but only on IL-6 at the late phase. These findings demonstrate the molecular mechanism of F759 arthritis can be recapitulated in silico and identify a possible therapeutic strategy for IL-6 amplifier-dependent chronic inflammatory diseases.

中文翻译：

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F759 小鼠 IL-6 依赖性类风湿性关节炎的计算机模型。

白介素 6 (IL-6) 放大器描述滑膜成纤维细胞中信号转导器和转录激活剂 3 (STAT3) 和 NF-κb 核因子 kappa B (NF-κB) 的同时激活，导致免疫细胞浸润进入 F759 小鼠的关节。其结果是出现一种类似于人类类风湿性关节炎的疾病。然而，STAT3 和 NF-κB 增强的转录激活如何导致 F759 关节炎的动力学和调节机制尚不清楚。我们在此证明 STAT3-NF-κB 复合物存在于细胞质和细胞核中，并在 IL-6 启动子区域的 NF-κB 结合位点周围积累，并建立了显示 IL-6 和 IL-17（白细胞介素 17）的计算机模型。 ) 信号传导促进 STAT3-NF-κB 复合物的形成，随后其与 NF-κB 靶基因的启动子区域结合，加速炎症反应，包括产生 IL-6、上皮调节蛋白和 CC 基序趋化因子配体 2 (CCL2) ，表型与体外实验一致。这种结合还促进滑膜中的细胞生长以及关节中 T 辅助 17 (Th17) 细胞和巨噬细胞的募集。抗 IL-6 阻断抗体治疗即使在晚期也能抑制炎症反应，但抗 IL-17 和抗 TNFα 抗体则不然。然而，抗IL-17抗体在早期表现出抑制作用，表明IL-6放大器在早期依赖于IL-6和IL-17刺激，但在后期仅依赖于IL-6。这些发现表明 F759 关节炎的分子机制可以在计算机中重现，并确定 IL-6 放大器依赖性慢性炎症性疾病的可能治疗策略。