Sinomenine increases adenosine A2A receptor and inhibits NF-κB to inhibit arthritis in adjuvant-induced-arthritis rats and fibroblast-like synoviocytes through α7nAChR
Sinomenine increases adenosine A2A receptor and inhibits NF-κB to inhibit arthritis in adjuvant-induced-arthritis rats and fibroblast-like synoviocytes through α7nAChR
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DOI：
10.1002/jlb.3ma0121-024rrrr
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发表时间：
2021-08-23
影响因子：
5.5
通讯作者：
Dong，Yan
中科院分区：
文献类型：
--
作者：
Yi，Lang;Ke，Junyu;Dong，Yan
青藤碱（SIN）是我国治疗类风湿性关节炎（RA）的临床药物。我们前期的研究发现SIN通过α 7烟碱乙酰胆碱受体（α 7 nAChR）抑制巨噬细胞的炎症反应。腺苷受体A2 A具有抗炎和免疫抑制作用。但SIN在RA中对α 7 nAChR的作用及对腺苷A2 A受体（A2 AR）的影响机制尚不清楚。本研究观察了SIN对大鼠关节炎（AIA）和滑膜成纤维细胞样细胞（FLS）的影响。以临床常用的抗关节炎药物吲哚美辛（Indo）和甲氨蝶呤（MTX）为对照。α 7 nAChR特异性激动剂尼古丁（Nicotine，Nic）作为靶向α 7 nAChR的对照。采用α-银环蛇毒素（α-BTX）、α 7 nAChR拮抗剂或小干扰RNA（siRNA）阻断或敲低α 7 nAChR。结果表明，SIN能降低AIA大鼠的关节炎指数、足爪体积、血沉（ESR）和血清TNF-α，α-BTX能减弱SIN和Nic的上述作用，但对Indo和MTX无明显影响。A2 AR在AIA大鼠滑膜中的表达下降，SIN干预后A2 AR的表达明显增加。LPS或TNF-α可降低FLS中A2 AR的表达，SIN可增加A2 AR的表达，SIN可增加cAMP的表达。SIN抑制LPS诱导的FLS中MCP-1、IL-6和血管内皮生长因子的表达。SIN可抑制NF-κB的活化。同时，α-BTX或α 7 nAChR siRNA可阻断SIN对FLS的上述作用。结果提示，A2 AR在滑膜和FLS中的表达与AIA大鼠关节炎的进展和FLS的激活呈负相关。SIN通过α 7 nAChR增加AIA大鼠和FLS的A2 AR，抑制NF-κB通路的激活。
Sinomenine (SIN) is a clinical drug for treating rheumatoid arthritis (RA) in China. Our previous study found SIN inhibited inflammation via alpha7 nicotinic acetylcholine receptor (α7nAChR) in macrophages in vitro. Adenosine receptor A2Ahas anti-inflammatory and immunosuppressive function. However, the mechanisms of SIN acting on α7nAChR and the effect on adenosine A2Areceptor (A2AR) in RA are not clear. In the present study, the effects of SIN on adjuvant-induced-arthritis (AIA) rats in vivo and on fibroblast-like synoviocytes (FLSs) in vitro were investigated. Indomethacin (Indo) and methotrexate (MTX), the clinical anti-arthritis drugs, were used as controls. Nicotine (Nic), a specific agonist of α7nAChR, was used as a control for targeting α7nAChR. Alpha-bungarotoxin (α-BTX), the antagonist of α7nAChR or small interference RNA (siRNA) was used to block or knock down α7nAChR. Results showed that SIN decreased arthritis index, hind paw volume, erythrocyte sedimentation (ESR) and serum TNF-α in AIA rats, and α-BTX attenuated the earlier-mentioned effects of SIN and Nic, but not Indo and MTX. The expressions of A2AR in synovium declined in AIA rats, but remarkably increased after the intervention of SIN. The expression of A2AR decreased by LPS or TNF-α, but increased by SIN; cAMP also increased by SIN in FLSs in vitro. SIN inhibited the expression of MCP-1, IL-6, and vascular endothelial growth factor in LPS-induced FLSs. SIN inhibited the activation of NF-κB. Meanwhile, α-BTX or α7nAChR siRNA blocked the earlier-mentioned effects of SIN in FLSs. Results suggested the expressions of A2AR in synovium and FLSs are negatively correlated with the arthritis progression of AIA rats and the activation of FLSs. SIN increases A2AR and inhibits the activation of NF-κB pathway via α7nAChR in AIA rats and FLSs.