State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
Int Immunopharmacol. 2018 Dec;65:233-243. doi: 10.1016/j.intimp.2018.10.015. Epub 2018 Oct 15.
Imbalance of Treg/Th17 and chronic synovitis characterized by the recruitment and infiltration of inflammatory cells are the typical features of rheumatoid arthritis (RA). IL-6 promotes the differentiation and function of Th17 cells, which contributes to the imbalance of Treg/Th17 and aggravates lymphocytic infiltration in joints. DC32, a dihydroartemisinin derivative, was found to have anti-inflammatory and immunosuppressive activities in previous study. The aim of this study is to evaluate the effects and mechanisms of DC32 in immunodeficiency and inflammatory infiltration of RA. In vivo, the antirheumatic effect of DC32 was evaluated in a collagen-induced arthritis (CIA) mouse model in DBA/1 mice. The percentages of Treg and Th17 and transcription of IL-6 in the spleen were assayed. In vitro, a coculture system of ConA-activated lymphocytes and fibroblast-like synoviocytes (FLSs) from rat with adjuvant arthritis (AA) was established. The effects and mechanisms of DC32 on synovitis were investigated. It was shown that DC32 inhibited footpad swelling and lymphocytic infiltration in mice with CIA and significantly restored the Treg/Th17 balance by reducing the transcription of IL-6 in splenocytes. DC32 significantly inhibited the lymphocyte-induced invasion and migration of FLSs by decreasing the secretion of MMPs (MMP-2, MMP-3) in vitro. DC32 also reduced the transcription of chemokines (CXCL12, CX3CL1) and IL-6 in FLSs, as well as IL-6 levels in the supernatant. These results demonstrated that DC32 may attenuate RA by restoring Treg/Th17 balance and inhibiting lymphocytic infiltration through downregulation of the expression and transcription of IL-6. This study supports the potential of DC32 to down-regulate IL-6 for the treatment of RA and other related autoimmune diseases.
调节性 T 细胞 (Treg)/辅助性 T 细胞 17（Th17）失衡和以炎症细胞募集及浸润为特征的慢性滑膜炎是类风湿关节炎 (RA) 的典型特征。白细胞介素-6 (IL-6) 促进 Th17 细胞的分化和功能，导致 Treg/Th17 失衡，并加重关节淋巴细胞浸润。二氢青蒿素衍生物 DC32 在先前的研究中被发现具有抗炎和免疫抑制作用。本研究旨在评估 DC32 在 RA 免疫缺陷和炎症浸润中的作用和机制。在体内，通过胶原诱导关节炎 (CIA) 小鼠模型评估 DC32 在 DBA/1 小鼠中的抗风湿作用。检测脾中 Treg 和 Th17 的百分比和 IL-6 的转录。在体外，建立了佐剂关节炎 (AA) 大鼠的 ConA 激活淋巴细胞和纤维母细胞样滑膜细胞 (FLS) 的共培养系统。研究了 DC32 对滑膜炎的作用和机制。结果表明，DC32 抑制 CIA 小鼠足垫肿胀和淋巴细胞浸润，并通过降低脾细胞中 IL-6 的转录显著恢复 Treg/Th17 平衡。DC32 还通过减少 MMPs（MMP-2、MMP-3）在体外的分泌，显著抑制淋巴细胞诱导的 FLSs 侵袭和迁移。DC32 还降低了 FLSs 中趋化因子 (CXCL12、CX3CL1) 和 IL-6 的转录以及上清液中的 IL-6 水平。这些结果表明，DC32 通过下调 IL-6 的表达和转录，可能通过恢复 Treg/Th17 平衡和抑制淋巴细胞浸润来减轻 RA。本研究支持 DC32 通过下调 IL-6 用于治疗 RA 和其他相关自身免疫性疾病的潜力。
