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小檗胺对系统性红斑狼疮小鼠的免疫调节作用

王慧莲, 展俊平^*, 苗喜云, 孟庆良, 马俊福

河南省中医院风湿病科，郑州 450053

摘要

系统性红斑狼疮(systemic lupus erythematosus, SLE)是有多种并发症的自身免疫性疾病，其确切病因尚不清楚，治疗方法包括激素等药物治疗、血浆置换及免疫吸附治疗以及靶向生物治疗等。小檗胺(berbamine, BBM)是一种具有多种生物学功能的细胞免疫促进剂，但其是否对SLE有免疫调节和治疗作用尚未见报道，本研究对这一问题进行探讨。实验动物分为对照组，模型组，阳性药物组，低、中、高浓度BBM组，对照组为C57BL/6J野生小鼠腹腔注射生理盐水，模型组为MRL/lpr狼疮模型小鼠腹腔注射生理盐水，阳性药物组为模型小鼠灌胃给予硫酸羟氯喹片[纷乐，150 mg/(kg·d)]，BBM组为模型小鼠分别灌胃给予不同浓度BBM [20、50、100 mg/(kg·d)]。治疗8周后，眼眶后静脉采血，使用ELISA检测抗双链DNA(double-stranded DNA, dsDNA)抗体、抗核抗体(antinuclear antibody, ANA)、抗小核糖核蛋白/Sm (small nuclear ribonucleoprotein/Sm, snRNP/Sm)抗体水平。收集各组小鼠脾脏组织，流式细胞术检测Th1/Th2比值。提取脾脏总RNA和总蛋白，分别进行qRT-PCR、Western blot检测T-box转录因子T-bet、GATA结合蛋白3 (GATA binding protein 3, GATA3)的mRNA和蛋白水平。血常规检测各组小鼠血液中白细胞的增殖情况。HE染色检测各组小鼠肾组织病理学变化。与模型组相比，BBM组的ANA、抗dsDNA抗体、抗snRNP/Sm抗体水平显著下降。模型组的Th1/Th2比值显著下降，BBM干预后逆转了Th1/Th2比值的下降。与对照组相比，模型组中T-bet表达水平显著下降，GATA3的表达水平显著上调。与模型组相比，BBM干预后的T-bet表达水平显著上升，GATA3的表达水平下降。模型组小鼠的白细胞数量显著下降，BBM处理后的白细胞数量显著增加。模型组肾小球系膜及内皮细胞明显增生，扩张的毛细血管中可见透明样血栓，肾间质内炎症细胞浸润明显；中、高浓度BBM干预后，炎症细胞浸润及毛细血管血栓明显减少。以上结果表明，BBM对SLE有一定的免疫调节作用和促进白细胞增殖的作用。

关键词： 小檗胺; 系统性红斑狼疮; 免疫调节

The immunomodulatory effect of berbamine on mice with systemic lupus erythematosus

WANG Hui-Lian, ZHAN Jun-Ping^*, MIAO Xi-Yun, MENG Qing-Liang, MA Jun-Fu

Department of Rheumatology, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou 450053, China

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease accompanied by various complications, and the exact etiology remains unclear. Treatments for SLE encompass hormone therapy, plasma exchange and immunoadsorption, and targeted biological therapies. Berbamine (BBM), a cellular immunopotentiator with diverse biological functions, has not been reported to have immunomodulatory and therapeutic effects on SLE. The mice were divided into control group, model group, positive control group, low, medium and high BBM groups. In control group, C57BL/6J wild mice received intraperitoneal injection of saline. In model group, MRL/lpr lupus mice were treated with intraperitoneal injection of saline. In positive control group, MRL/lpr lupus mice received intragastric administration of hydroxychloroquine sulfate tablets [Plaquenil, 150 mg/(kg·d)]. In BBM groups, MRL/lpr lupus mice received intragastric administration of different concentration of BBM respectively [20 mg/(kg·d), 50 mg/(kg·d), 100 mg/(kg·d)]. After 8 weeks of treatment, blood was collected from the retro-orbital venous plexus, and ELISA was used to detect the levels of anti- double-stranded DNA (dsDNA) antibodies, antinuclear antibodies (ANA), and anti-small nuclear ribonucleoprotein/Sm (snRNP/Sm) antibodies. Spleen tissues were collected for analysis of Th1/Th2 ratio by flow cytometry. The RNA and protein of spleen were extracted, and the levels of T-box transcription factor T-bet and GATA3 (GATA binding protein 3) mRNA and protein were detected by qRT-PCR and Western blot. The proliferation of white blood cells in the blood was tested by blood routine test. The histopathological changes of kidneys of each group were detected by HE staining. Compared with the model group, the levels of ANA, anti-dsDNA, and anti-snRNP/Sm antibodies were significantly reduced in the BBM-treated groups. The Th1/Th2 ratio was significantly decreased in the model group, but reversed by BBM. Compared with the control group, T-bet expression was significantly downregulated, while GATA3 expression was significantly upregulated in the model group. After BBM intervention, T-bet expression significantly increased, while GATA3 expression decreased compared with the model group. The number of white blood cells significantly decreased in the model group, and increased in the BBM-treated groups. In the model group, the glomerular mesangial and endothelial cells showed significant hyperplasia, clear thrombus was observed in the dilated capillaries, and inflammatory cells infiltrated in the renal interstitium. In medium and high BBM groups, the infiltration of inflammatory cells and capillary thrombosis were significantly decreased. In conclusion, BBM exhibits certain immunomodulatory effects on SLE and promotes the proliferation of white blood cells.

Key words: berbamine; systemic lupus erythematosus; immunomodulation

收稿日期：　　录用日期：

通讯作者：展俊平　　E-mail:

DOI: 10.13294/j.aps.2025.0043

引用本文：

王慧莲, 展俊平, 苗喜云, 孟庆良, 马俊福. 小檗胺对系统性红斑狼疮小鼠的免疫调节作用[J]. 生理学报 2025; 77 (3): 432-440.

WANG Hui-Lian, ZHAN Jun-Ping, MIAO Xi-Yun, MENG Qing-Liang, MA Jun-Fu. The immunomodulatory effect of berbamine on mice with systemic lupus erythematosus. Acta Physiol Sin 2025; 77 (3): 432-440 (in Chinese with English abstract).