The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China.
Central Laboratory, Nanjing Hospital of Chinese Medicine, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Front Immunol. 2018 Sep 26;9:2228. doi: 10.3389/fimmu.2018.02228. eCollection 2018.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthropathy associated with articular damage and attendant comorbidities. Even although RA treatment has advanced remarkably over the last decade, a significant proportion of patients still do not achieve sustained remission. The cause of RA is not yet known despite the many potential mechanisms proposed. It has been confirmed that RA is associated with dysregulated immune system and persistent inflammation. Therefore, management of inflammation is always the target of therapy. Sinomenine (SIN) is the prescription drug approved by the Chinese government for RA treatment. A previous study found that SIN was a robust anti-inflammation drug. In this study, we screened the different secretory cytokines using inflammation antibody arrays and qRT-PCR in both LPS-induced and SIN-treated RAW264.7 cells followed by evaluation of the ability of SIN to modulate cytokine secretion in a cell model, collagen-induced arthritis (CIA) mouse model, and RA patients. Several clinical indexes affecting the 28-joint disease activity score (DAS28) were determined before and after SIN treatment. Clinical indexes, inflammatory cytokine secretion, and DAS28 were compared among RA patients treated with either SIN or methotrexate (MTX). To explore the mechanism of SIN anti-inflammatory function, RA-associated monocyte/macrophage subsets were determined using flow cytometry in CIA mouse model and RA patients, both treated with SIN. The results demonstrated that SIN regulated IL-6, GM-CSF, IL-12 p40, IL-1α, TNF-α, IL-1β, KC (CXCL1), Eotaxin-2, IL-10, M-CSF, RANTES, and MCP-1 secretion and and reduced RA activity and DAS28 in a clinical setting. Furthermore, SIN attenuated CD11bF4/80CD64 resident macrophages in the synovial tissue, CD11bLy6CCD43 macrophages in the spleen and draining lymph nodes of CIA mice. The percentage of CD14CD16 peripheral blood mononuclear cells was reduced by SIN in RA patients. These data indicated that SIN regulates the secretion of multiple inflammatory cytokines and monocyte/macrophage subsets, thereby suppressing RA progression. Therefore, along with MTX, SIN could be an alternative cost-effective anti-inflammatory agent for treating RA.
类风湿关节炎（RA）是一种慢性自身免疫性炎症性关节病，与关节损伤和伴随的合并症有关。尽管在过去十年中，RA 的治疗取得了显著进展，但仍有相当一部分患者无法持续缓解。尽管提出了许多潜在的机制，但 RA 的病因仍不清楚。已经证实 RA 与免疫系统失调和持续炎症有关。因此，炎症的管理始终是治疗的目标。青藤碱（SIN）是中国政府批准用于 RA 治疗的处方药。先前的一项研究发现，SIN 是一种强大的抗炎药。在这项研究中，我们使用炎症抗体阵列和 qRT-PCR 在 LPS 诱导和 SIN 处理的 RAW264.7 细胞中筛选了不同的分泌细胞因子，然后评估了 SIN 在细胞模型、胶原诱导性关节炎（CIA）小鼠模型和 RA 患者中调节细胞因子分泌的能力。在 SIN 治疗前后测定了影响 28 关节疾病活动评分（DAS28）的几个临床指标。比较了接受 SIN 或甲氨蝶呤（MTX）治疗的 RA 患者的临床指标、炎症细胞因子分泌和 DAS28。为了探索 SIN 抗炎功能的机制，我们使用流式细胞术在 CIA 小鼠模型和接受 SIN 治疗的 RA 患者中确定了与 RA 相关的单核细胞/巨噬细胞亚群。结果表明，SIN 调节了 IL-6、GM-CSF、IL-12 p40、IL-1α、TNF-α、IL-1β、KC（CXCL1）、Eotaxin-2、IL-10、M-CSF、RANTES 和 MCP-1 的分泌，并降低了临床环境中的 RA 活性和 DAS28。此外，SIN 减弱了 CIA 小鼠滑膜组织中的 CD11bF4/80CD64 驻留巨噬细胞、脾脏和引流淋巴结中的 CD11bLy6CCD43 巨噬细胞。SIN 还降低了 RA 患者外周血单核细胞中的 CD14CD16 比例。这些数据表明，SIN 调节多种炎症细胞因子和单核细胞/巨噬细胞亚群的分泌，从而抑制 RA 的进展。因此，SIN 可以与 MTX 一起作为治疗 RA 的一种具有成本效益的替代抗炎药物。
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