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Deficiency of O-linked-glycosylation regulates activation of T cells and aggravates Concanavalin A-induced liver injury.
Toxicology ( IF 4.5 ) Pub Date : 2020-02-17 , DOI: 10.1016/j.tox.2020.152411
Xiaohua Hao 1 , Meixin Gao 2 , Lingling He 1 , Xiaohui Ye 3 , Junru Yang 1 , Fuyang Zhang 2 , Ran Liu 4 , Hongshan Wei 5
Affiliation  

OBJECTIVE Protein glycosylation is involved in immunological recognition and immune cell activation. The role of O-glycosylation in Concanavalin A (Con A)-induced autoimmune hepatitis (AIH) was elucidated in the present study. METHODS Mice were intravenously injected with Con A (10 mg/kg) to establish an AIH mouse model. Here, 24 h prior to administration of Con A, experimental mice were intragastrically administrated with O-glycosylation inhibitor (benzyl-α-GalNAc) at doses of 1 and 5 mg/kg, respectively, while control mice were administrated with the same volume of saline. Before and after administration of Con A for 6 and 12 h, mice were sacrificed and their plasma and livers were collected to score liver injury. Peripheral blood, spleen, and thymus were collected for flow cytometry analysis. The expression levels of neutrophilic alkaline phosphatase-3 (NALP3) and NALP6 in liver were evaluated as well. RESULTS Pre-treatment with benzyl-α-GalNAc increased the serum transaminase levels and induced more infiltration and necrosis in livers of Con A administrated mice. The levels of some pro-inflammation cytokines also increased in administrated mice. In addition, pretreatment with benzyl-α-GalNAc up-regulated the expression levels of NALP3 and NALP6. And benzyl-α-GalNAc inhibited the levels of apoptosis of thymus cells and influenced activation of T cells in peripheral blood and spleen of Con A administrated mice, especially that accelerated the physiological progression of CD4+CD25-CD69+ subset. CONCLUSION The present research demonstrated that benzyl-α-GalNAc aggravated Con A-induced AIH, and the role of the O-glycosylation inhibitor as the aggravation may be related to regulation of the levels of cytokines, as well as influencing proliferation of T cells.

中文翻译:

O-连接糖基化的缺乏调节T细胞的活化并加重伴刀豆球蛋白A诱导的肝损伤。

目的蛋白糖基化参与免疫学识别和免疫细胞活化。在本研究中阐明了O-糖基化在伴刀豆球蛋白A(Con A)诱导的自身免疫性肝炎(AIH)中的作用。方法给小鼠静脉注射Con A(10 mg / kg),建立AIH小鼠模型。在此,在Con A给药前24小时,分别以1和5 mg / kg的剂量在实验小鼠的胃内给予O-糖基化抑制剂(苄基-α-GalNAc),而在对照组小鼠中给予相同体积的C-盐水。在施用Con A 6小时和12小时之前和之后,处死小鼠并收集其血浆和肝脏以评分肝损伤。收集外周血,脾脏和胸腺进行流式细胞术分析。还评估了嗜中性碱性磷酸酶3(NALP3)和NALP6在肝脏中的表达水平。结果用苄基-α-GalNAc预处理可提高Con A给药小鼠肝脏的血清转氨酶水平,并引起更多的浸润和坏死。在施用的小鼠中,某些促炎细胞因子的水平也增加。此外,用苄基-α-GalNAc预处理可上调NALP3和NALP6的表达水平。苄基-α-GalNAc抑制Con A给药小鼠的胸腺细胞凋亡水平,并影响其外周血和脾脏T细胞的活化,特别是促进了CD4 + CD25-CD69 +亚群的生理进程。结论本研究表明,苄基-α-GalNAc加剧了Con A诱导的AIH,
更新日期:2020-02-20
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