Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
Biochem Biophys Res Commun. 2019 Sep 17;517(2):338-345. doi: 10.1016/j.bbrc.2019.07.087. Epub 2019 Jul 26.
Artemisinin is a potent anti-malarial agent that plays a potent role in regulating inflammatory disorders. NEK7 is a major interacting partner with NLRP3 in NLRP3 inflammasome. The aim of this study was to clarify the anti-inflammatory effect of artemisinin on activation of uric acid-induced NLRP3 inflammasome through regulation of NEK7.
Human macrophage U937 cells treated with lipopolysaccharide (LPS), monosodium urate (MSU) crystals, or artemisinin were used in in vitro study. Intracellular potassium (K) level was measured in U937 cells treated with and without artemisinin. Expression of target genes or proteins NEK7, NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and NF-κB signaling molecules was measured. MSU crystal-induced arthritis model was used for in vivo study.
Gout patients showed higher NLRP3 and NEK7 mRNA expression, compared to controls. Enhanced expression of NLRP3, caspase-1, and IL-1β was noted in macrophages treated with LPS (10 ng/ml) and MSU crystals (0.1 mg/ml), which was markedly suppressed by treatment with artemisinin (1, 10, and 100 μM). Artemisinin significantly inhibited interaction between NLRP3 and NEK7 in NLRP3 inflammasome activation. Artemisinin (10 and 100 μM) attenuated intracellular K efflux in macrophages stimulated with LPS and MSU crystals. Artemisinin suppressed foot and ankle swelling in MSU crystal-induced arthritis mice.
This study revealed that artemisinin inhibited activation of NLRP3 inflammasome by suppressing interaction between NEK7 and NLRP3 in uric acid-induced inflammation.
青蒿素是一种有效的抗疟药物，在调节炎症性疾病方面发挥着重要作用。NEK7 是 NLRP3 炎症小体中与 NLRP3 相互作用的主要伙伴。本研究旨在通过调节 NEK7 阐明青蒿素对尿酸诱导的 NLRP3 炎症小体激活的抗炎作用。
在体外研究中使用了人巨噬细胞 U937 细胞，用脂多糖（LPS）、单钠尿酸盐（MSU）晶体或青蒿素处理。在有无青蒿素处理的 U937 细胞中测量细胞内钾（K）水平。测量靶基因或蛋白 NEK7、NLRP3、ASC、半胱天冬酶-1、白细胞介素-1β（IL-1β）和 NF-κB 信号分子的表达。使用 MSU 晶体诱导的关节炎模型进行体内研究。
与对照组相比，痛风患者 NLRP3 和 NEK7 mRNA 表达较高。用 LPS（10ng/ml）和 MSU 晶体（0.1mg/ml）处理的巨噬细胞中观察到 NLRP3、半胱天冬酶-1 和 IL-1β 的表达增强，用青蒿素（1、10 和 100µM）处理后明显受到抑制。青蒿素显著抑制 NLRP3 炎症小体激活中 NLRP3 和 NEK7 之间的相互作用。青蒿素（10 和 100µM）抑制了 LPS 和 MSU 晶体刺激的巨噬细胞中细胞内 K 外流。青蒿素抑制了 MSU 晶体诱导关节炎小鼠的足踝关节肿胀。
本研究表明，青蒿素通过抑制尿酸诱导的炎症中 NEK7 和 NLRP3 之间的相互作用抑制了 NLRP3 炎症小体的激活。
