A novel combination of astilbin and low-dose methotrexate respectively targeting A2AAR and its ligand adenosine for the treatment of collagen-induced arthritis
A novel combination of astilbin and low-dose methotrexate respectively targeting A2AAR and its ligand adenosine for the treatment of collagen-induced arthritis
复制标题
落新妇苷和低剂量甲氨蝶呤的新型组合，分别靶向 A2AAR 及其配体腺苷，用于治疗胶原诱导的关节炎。
DOI：
10.1016/j.bcp.2018.01.033
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发表时间：
2018-07-01
影响因子：
5.8
通讯作者：
Xu, Qiong
中科院分区：
文献类型：
--
作者：
Ma, Yuxiang;Gao, Zhe;Xu, Qiong
甲氨蝶呤（MTX）广泛用于类风湿关节炎（RA）的治疗，但经常出现严重的不良反应。因此，临床上常采用小剂量MTX与其他药物联合用药。在这项研究中，我们研究了落新妇苷和低剂量MTX组合对DBA/1 J小鼠胶原诱导的关节炎的改善作用。结果表明，联合用药组的临床评分、发病率、足肿胀、关节病变及类风湿因子均较单用MTX或落新妇苷组明显减轻。血清中升高的抗体（IgG、IgG 1、IgG 2a、IgM和抗胶原IgG）和促炎细胞因子（IL-1 β、IL-6、TNF-α、IFN-γ和IL-17 A）被显著抑制，而抗炎细胞因子IL-10通过联合治疗被增强。进一步的研究表明，联合治疗显著降低了Th 1和Th 17细胞分化，并增加了Treg细胞分化。机制分析表明联合治疗显著抑制了Con A激活的MAPK和炎症转录信号。此外，MTX激活腺苷释放和落新妇苷特异性上调A（2A）腺苷受体（A（2A）AR）表达的同时，这很可能有助于联合治疗的协同效应。A（2A）AR的特异性拮抗剂ZM 241385可显著阻断联合治疗对T细胞功能和下游通路的影响。这些结果提示落新妇苷可能通过增强A（2A）AR/腺苷系统和降低ERK/NF κ B/STAT信号而成为小剂量MTX联合治疗RA的有效药物。
Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment with frequently serious adverse effects. Therefore, combination of low-dose MTX with other drugs is often used in clinic. In this study, we investigated the improvement of astilbin and low-dose MTX combination on collagen-induced arthritis in DBA/1J mice. Results showed that the clinic score, incidence rate, paw swelling, pathological changes of joints and rheumatoid factors were more alleviated in combination therapy than MTX or astilbin alone group. Elevated antibodies (IgG, IgG1, IgG2a, IgM and anti-collagen IgG) and pro-inflammatory cytokines (IL-1 beta, IL-6, TNF-alpha, IFN-gamma and IL-17A) in serum were significantly inhibited, while anti-inflammatory cytokine, IL-10, was enhanced by combination therapy. Further studies indicated that combination therapy significantly decreased Th1 and Th17 cell differentiation and increased Treg cell differentiation. Mechanisms analysis demonstrated combination therapy greatly inhibited Con A-activated MAPK and inflammatory transcriptional signals. Moreover, MTX activated adenosine release and astilbin specifically up-regulated A(2A) adenosine receptor (A(2A)AR) expression simultaneously, which most probably contributed to the synergistic efficacy of combination therapy. ZM241385, a specific antagonist of A(2A)AR, greatly blocked the effects of combination therapy on T cell functions and downstream pathways. All these findings suggest that astilbin is a valuable candidate for low-dose MTX combined therapy in RA via increasing A(2A)AR/adenosine system and decreasing ERK/NFKB/STATs signals.