脑CYP2E1参与脂多糖诱导的神经元损伤  

Involvement of brain CYP2E1in damage to neuronal cells induced by lipopolysaccharide

作　　者：那淑芳 姚慧[1] 李杰[1] 杨哲琼[1] 乐江[1] 

机构地区：[1]武汉大学基础医学院药理学系,湖北武汉430071

出　　处：《中国药理学通报》2016年第7期932-937,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 30600773;No 31271327)

摘　　要：目的研究脂多糖(LPS)所致炎症与脑细胞色素P4502E1和CYP2E1之间的相互影响。方法采用具有胆碱能神经元特征的IMR-32人神经母细胞瘤细胞系,分别给予低剂量(0.1 mg·L^(-1))和高剂量(1.0 mg·L^(-1))LPS处理24 h,检测LDH和SOD活性。在LPS处理前45 min,分别加入p38抑制剂SB203580和ERK抑制剂U0126处理IMR-32细胞,观察MAPK信号系统对神经元CYP2E1表达的影响。采用具有多巴胺能神经元特征的SH-SY5Y人神经母细胞瘤细胞系建立高表达CYP2E1细胞系,并与正常SH-SY5Y细胞同时给予低剂量(0.1 mg·L^(-1))和高剂量(1.0 mg·L^(-1))LPS处理24 h后检测LDH和SOD活性。结果与对照组相比,高剂量LPS处理IMR-32细胞,SOD的活力下降15.0%(P<0.01),LDH上升1.38倍(P<0.01),CYP2E1 mRNA升高1.25倍(P<0.01),蛋白水平升高1.19倍(P<0.05)。p38和ERK抑制剂可拮抗高剂量LPS对CYP2E1的诱导作用。低剂量LPS处理CYP2E1高表达SH-SY5Y细胞,LDH的升高幅度较非高表达的对照组上升了1.28倍(P<0.01),SOD活力下降幅度增加了3.53倍(P<0.01);高剂量LPS使得CYP2E1高表达SH-SY5Y细胞LDH的升高幅度较非高表达的对照组上升了1.54倍(P<0.01),SOD活力下降幅度增加了2.17倍(P<0.01)。结论 LPS可上调神经元所表达的CYP2E1水平,其调控作用可能与ERK和p38信号传导通路相关。高表达CYP2E1加剧LPS对神经元的损伤,提示CYP2E1参与了炎症所致神经细胞损伤的病理过程。Aim To investigate the interactions be-tween the neuroinflammation caused by lipopolysaccha-ride（LPS） and brain CYP2E1.Methods The human cholinergic neuroblastoma cell line IMR-32 was treated with LPS （ 0.1 mg · L-1 , 1.0 mg · L-1 ） , and the LDH and SOD activities were determined after 24 h in-cubation .In order to determine the roles of MAPK sig-naling pathway in the regulation of CYP 2E1 by LPS, the IMR-32 cells were treated with p38 pathway inhibi-tor SB203580 or ERK pathway inhibitor U 0126 for 45 min before the incubation with LPS .The human do-paminergic neuroblastoma cell line SH-SY5Y with CYP2 E1 over-expression was established . The LDH and SOD activities were determined in SH-SY5 Y cells over-expressed CYP2 E1 and control cells treated with LPS（0.1 mg· L-1 , 1.0 mg· L-1 ） for 24 h.Results The levels of LDH in IMR-32 cells treated with high-dose LPS were increased by 1.38-fold （ P 〈0.01 ） compared with the control group , and the levels of SOD reduced by 15.0%（ P 〈0.01 ） .Compared with the control, CYP2E1 mRNA and protein levels in IMR-32＆nbsp;cells treated with high-dose LPS were increased by 1.25-fold（P〈0.01） and 1.19-fold（P〈0.05）.The up-regulation of CYP2E1 by LPS could be attenuated by SB203580 and U0126 pretreatment.Compared with the control cells, the CYP2E1 over-expression in-creased LDH levels by 1.28-fold （ P〈0.01 ） and de-creased SOD levels by 3.53-fold （ P〈0.01 ） after the low-dose of LPS treatment .The CYP2E1 over-expres-sion increased LDH levels by 1.54-fold （ P 〈0.01 ） and decreased SOD levels by 2.17-fold（ P〈0.01） af-ter the high-dose of LPS treatment , compared with the control cells.Conclusions LPS can induce CYP2E1 mRNA and protein levels , and the p38 and ERK sig-naling pathway may be involved in the regulation .The elevated CYP2 E1 levels aggravate the damage to neuro-nal cells caused by LPS .Brain CYP2E1 may be an im-portant contributing factor to the pathological process of neuroinflammatory injury .

关 键 词：脂多糖 炎症 神经元 ERK信号传导通路 p38信号传导通路 

分 类 号：R322.81[医药卫生—人体解剖和组织胚胎学] R329.25[医药卫生—基础医学]