洛美利嗪调控小鼠巨噬细胞极化的机制研究  

Lomerizine regulates mouse macrophage polarization in vitro

作　　者：唐慧瑢 古丽再帕尔·托合尼亚孜 陈东馨 姜洪超 赵文娟[1] 孙磊[1] 钱峰[1] TANG Hui-rong;GVLZAPAR Tohniyaz;CHEN Dong-xin;JIANG Hong-chao;ZHAO Wen-juan;SUN Lei;QIAN Feng(Pharm-X Center,Engineering Research Center of Cell and Therapeutic Antibody,School of Pharmacy,Shanghai Jiaotong University,Shanghai 200240,China)

机构地区：[1]上海交通大学药学院细胞与治疗抗体工程研究中心,上海200240

出　　处：《中国病理生理杂志》2021年第7期1153-1162,共10页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81973329,No.82073858,No.81773741);上海交通大学科技创新专项资金资助项目(No.19X160010005)。

摘　　要：目的:探究洛美利嗪对小鼠巨噬细胞M1型和M2型极化的调控作用及分子机制。方法:采用RTqPCR及Western blot实验检测洛美利嗪对小鼠骨髓来源的巨噬细胞和Raw 264.7小鼠巨噬细胞M1和M2型极化的影响;Western blot实验检测洛美利嗪对调控巨噬细胞极化的丝裂原活化蛋白激酶(MAPK)、核因子κB(NF-κB)和信号转导及转录激活因子6(STAT6)信号通路的影响。结果:洛美利嗪能够显著抑制脂多糖(LPS)诱导的M1型巨噬细胞炎症因子肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)和IL-1β的产生(P<0.01),且剂量依赖性地降低M1型极化标志物诱导型一氧化氮合酶(iNOS)的表达(P<0.05),同时促进IL-4诱导的M2型巨噬细胞标志物几丁质酶3样蛋白3(CHI3L3/Ym-1)、Fizz-1(found in inflammatory zone-1)和精氨酸酶1(Arg-1)的mRNA和蛋白表达(P<0.05)。洛美利嗪能够剂量依赖性地抑制MAPK信号通路中p38 MAPK、细胞外信号调节激酶1/2(ERK1/2)和c-Jun氨基末端激酶1/2(JNK1/2)的磷酸化以及NF-κB信号通路中NF-κB p65的磷酸化,并促进核因子κB抑制因子α(IκBα)的表达(P<0.05),进而介导巨噬细胞极化。结论:洛美利嗪可以通过调控MAPK和NF-κB信号通路进而剂量依赖性地抑制小鼠巨噬细胞M1型极化,同时洛美利嗪还可以显著促进M2型极化。AIM:To investigate the regulatory effect of lomerizine on mouse macrophage polarization in vitro,and to explore its possible molecular mechanisms.METHODS:The effects of lomerizine on M1 and M2 polarization of mouse bone marrow-derived macrophages and Raw 264.7 mouse macrophages were measured by RT-qPCR and Western blot.Western blot was also used to detect the effect of lomerizine on the signaling pathways of mitogen-activated protein ki-nase(MAPK),nuclear factor-κB(NF-κB)and signal transducer and activator of transcription 6(STAT6)involved in macrophage polarization.RESULTS:Lomerizine reduced the expression of tumor necrosis factor-α(TNF-α),interleu-kin-6(IL-6),IL-1β,and M1 marker inducible nitric oxide synthase(iNOS)induced by lipopolysaccharide(LPS),but increased the expression of M2 markers chitinase 3-like protein 3(CHI3L3/Ym-1),arginase-1(Arg-1)and found in in-flammatory zone-1(Fizz-1)induced by IL-4(P<0.05).Lomerizine dose-dependently down-regulated the phosphorylation of p38 MAPK,extracellular signal-regulated kinase 1/2(ERK1/2),c-Jun N-terminal kinase 1/2(JNK1/2)and p65 NF-κB,but up-regulated nuclear factor-κB inhibitorα(IκBα)expression(P<0.05).CONCLUSION:Lomerizine dose-de-pendently inhibits the M1 polarization of mouse macrophages probably through modulating MAPK and NF-κB signaling pathways,and significantly promotes the M2 polarization.

关 键 词：洛美利嗪 巨噬细胞 极化 MAPK信号通路 NF-ΚB信号通路 

分 类 号：R329.25[医药卫生—人体解剖和组织胚胎学] R363.2[医药卫生—基础医学]