摘要
目的:随着科技的进步和发展,各类办公自动化设备、移动通讯设备、家用电器迅速进入我们的生活,使我们更多地暴露于电磁辐射中。从上世纪60年代开始国际社会已经把关注的目光集中到微波的生物效应研究。越来越多的电磁辐射的生物效应、效应机理及其防护正逐渐成为研究的热点课题。根据我室以往的研究,微波辐射致伤的敏感靶器官包括神经系统、血液系统、生殖系统、免疫系统等,尤以对神经系统的影响最为显著。小胶质细胞是中枢神经系统中重要的免疫细胞,参与神经免疫调节,其最显著的生物学特性就是在中枢神经系统受到各种病理刺激时发生活化。活化的小胶质细胞对神经元以及中枢神经系统内环境发挥着重要的调节功能,小胶质细胞活化的调控机制十分广泛复杂。其中JAK-STAT信号转导途径是近年来新发现的一条参与神经免疫调节的信号传导通路。为此我们研究微波辐照能否激活小胶质细胞,JAK-STAT信号通路是否参与微波诱导的小胶质细胞活化,以及作用机制进行了研究。
方法:以平均功率密度90 mW/cm2的微波一次性辐照N9小胶质细胞,分别采用细胞免疫组织化学和流式细胞技术来检测小胶质细胞活化标志物OX-42的表达变化。用ELISA方法检测肿瘤坏死因子α,白介素1β在培养上清中的浓度,用Griess reaction方法检测培养上清中NO的释放。用RT-PCR方法检测iNOS的mRNA表达变化。用Western-blot检测小胶质细胞JAK1、JAK2、JAK3、STAT3蛋白质表达及磷酸化表达变化,用凝胶迁移率实验(Electrophoretic Mobility Shift Assay,EMSA)检测小胶质细胞STAT3的DNA结合活性的变化。
结果:
1. 90 mW/cm2的微波辐照N9小胶质细胞后,小胶质细胞形态发生明显变化,辐照后3h至24h小胶质细胞活化标志物OX-42表达增加,在辐照后6h表达最为明显。辐照后即刻至24h小胶质细胞TNF-α分泌明显增加,在辐照后3h达到高峰,而IL-1β无明显变化。微波辐照后即刻至24h内NO释放明显增加,iNOS mRNA表达增强,在辐照后6h达到高峰。
2. 90 mW/cm2的微波辐照N9小胶质细胞后,JAK1、JAK2、JAK3蛋白质磷酸化出现不同程度增加,并且其变化趋势各不相同。微波辐照后小胶质细胞STAT3磷酸化增强,其变化趋势与JAK2类似,STAT3核转位与DNA结合活性在辐照后6h至24h增加,并以12h最为明显。
3.使用JAK的抑制剂AG490及P6能显著抑制微波辐照后STAT3磷酸化以及与DNA的结合活性,可有效抑制了JAK家族的磷酸化。抑制炎性因子TNF-α,的分泌和NO的释放,减少iNOS的mRNA表达。减少微波诱导小胶质细胞活化标志物OX-42的表达。
结论:
1.在本实验条件下,微波辐射能诱导小胶质细胞活化,并且表现为持续活化,活化小胶质细胞分泌功能明显增强。
2.微波辐照可以使小胶质细胞JAK/STAT信号通路出现差别激活。JAK/STAT信号通路中各信号分子在小胶质细胞活化过程中的作用不同,其中JAK2、STAT3具有主要作用,JAK3可能也发挥一定作用,而JAK1作用不明显。
3.微波辐照后小胶质细胞活化,活化的小胶质细胞分泌大量细胞因子。JAK-STAT信号通路参与了微波辐射诱导的小胶质细胞活化过程。
Objectives: With the development of science and technology, more and more people are exposed to electromagnetic radiation, because of the popular use electrical appliances. Such as mobile phone and microwave oven steps into our daily life rapidly.The effects of electromagnetic fields (EMF) and microwave on the central nervous system (CNS) need to be evaluated. Microglia activation is an important component of physiological and pathological processes in CNS. The Janus kinase/signal transducer and activator of transcription (JAK /STAT) pathway play a central role in cytokine signal transduction and regulate various biological processes. We investigated the possible participation of JAK/STAT signaling system and activation of microglia after microwave exposure.
Methods: N9 murine microglia cells were irradiated by 90 mW/cm2 microwave, Expression of microglial membrane OX-42 was determined by immunocytochemical staining and flow cytometry. Secretion of TNF-α, IL-1βwas examined by ELISA and NO activity was determined by the Griess reaction. The expression of iNOS mRNA was determined by RT-PCR. Phosphorylation of JAK-STAT3 was tested using western blotting. STAT3 DNA binding activity was detected by EMSA.
Results:(1) After 90 mW/cm2 microwave exposure, the morphous of microglia changed significantly. OX-42, an activated microglia surface marker was gradually increased from 3h to 24h post microwave exposure and expressed at 6h time point obviously.The production of TNF-αwas increased from 0h to 24h and achieved peak level at 3h after microwave exposure.But the secretion IL-1βwas unchanged. The expression of of iNOS mRNA and release of NO increased in a time-dependent manner post microwave exposure,and achieved peak level at 3h time point. (2) After 90 mW/cm2 microwave exposure, the phosphorylation of JAK1, JAK2 and JAK3 was increased at different manner. The band of phosphorylated STAT3 was dected rapidly post microwave exposure, and the pattern was similar to phosphorylated-JAK2.A significant increase of STAT3 DNA-binding ability was noted from 6h to 24h after exposure, especially at 12h. (3)AG490 and P6, the specific JAK inhibitor, inhibited STAT3 translocation to nuclus and markedly reduced the activation of JAK and STAT3 in microwave -treated microglia. Furthermore, the expression of TNF-αand release of NO induced by microwave in microglia were reduced by AG490 and P6 pretreatment.The expression of iNOS mRNA decreased markedly in pretreatment with AG490 and P6.Lastly ,the FITC-labelled OX-42 cell counts declined after pretreatment with AG490 and P6.
Conclusions:(1) Microwave irradiation induced the activation of microglia in a persistent manner. Production of proinflammatory cytokines of activated microglia increased significantly after exposure to microwave. (2) Microwav irradiation activated JAK-STAT protein at a differential manner.The involvement of JAK-STAT signal pathway was not identical in microglia activation post microwave exposure.These results suggest that JAK2-STAT3 signaling pathway plays a critical role in microwave mediated activation of microglia, and JAK3 may participate in the activation,while JAK1 has no effect. (3) Microwave irradiation induced the activation of microglia and secretion of cytokine. The JAK2-STAT3 signaling pathway may participate in the pathogenesis of microwave-induced injury.
引文
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