OX40/OX40L mRNA在EAN中的表达及ROK抑制剂对其影响
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摘要
目的:吉兰-巴雷综合征(GBS)是一种常见的周围神经系统自身免疫性疾病,其病理改变主要为周围神经髓鞘脱失和炎性细胞浸润。实验性变态反应性神经炎(EAN)是研究GBS的理想动物模型,周围神经髓鞘蛋白抗原特异性CD4~+T细胞的活化是其发病关键。OX40/0X40L是新近发现的协同刺激分子,它们在维持CD4~+T细胞的增殖、分化和长期存活方面发挥重要作用。Rho/Rho激酶(ROK)信号通路是多系统疾病及损伤发生发展的重要病理途径,它可以促进T细胞迁移、炎性因子分泌、细胞凋亡和神经突触崩解,应用ROK抑制剂治疗后,多种炎性疾病症状明显改善。本实验通过观察0X40和OX40L mRNA在EAN大鼠坐骨神经、脾脏、外周血和淋巴结的动态表达变化及ROK抑制剂对其表达的影响,探讨OX40/0X40L与EAN发病的关系并以OX40/0X40L为切入点探讨ROK抑制剂治疗EAN的分子机制,为其临床应用奠定理论基础。
方法:54只Lewis大鼠随机分为EAN模型组(n=6,6,6),EAN+ROK抑制剂干预组(n=6,6,6),完全弗氏佐剂对照组(CFA)组(n=6,6,6)。EAN组大鼠用合成肽段P2 53-78aa+CFA+NS免疫,EAN+ROK抑制剂组从模型制作前两天腹腔注射法舒地尔注射液(25mg/kg.d)治疗。观察各组大鼠发病情况和组织病理学改变。分别在第9天、17天、26天处死动物取其坐骨神经根、脾脏、外周血单个核细胞和淋巴结,采用RT-PCR技术检测OX40和OX40LmRNA在各组织的表达水平。
结果:EAN组大鼠在抗原免疫后第17天达到发病高峰,OX40和OX40L mRNA在第9天(发病早期)和第17天时表达均较高,与第26天相比有显著差异(p＜0.05),各时间点与对照组相比有显著差异(p＜0.05);EAN+ROK抑制剂组大鼠与EAN组相比,其平均最高临床评分明显降低(p＜0.01),坐骨神经炎性细胞浸润和脱髓鞘减轻,OX40和OX40L在各时间点的表达减少(p＜0.05)。CFA组大鼠无症状。
结论:OX40/0X40L可能与EAN发病有关;ROK抑制剂可以减轻EAN发病程度,抑制OX40/0X40L的表达可能是其作用机制之一。
Objective Guillain-Barre Syndrome(GBS) is an autoimmune disease of the peripheral nervous system, characterized by multifocal demyelination and inflammation cells infiltration in peripheral nerves and spinal nerve roots._Experimental allergic neuritis(EAN) is a classical animal model to study pathogenetis of GBS. The activation of peripheral nervous myelin antigen specific CD4~+T cell play key roles in the development of EAN. OX40/OX40L is a new co-stimulatory molecules, it appears to be particularly important for regulating the extent of CD4~+ T cell expansion in the primary T cell respons. Rho/ROK plays an important role in various pathological processes, promoting the migration of T cells, inducing the secretion of inflammatory factors, and triggering cell apoptosis and synapse disintegration. Rho-kinase inhibitors may ameliorate the symptoms in many inflammatory diseases. In this study, through observing the expression of mRNA of OX40 and OX40L in the sciatic nerve, spleen, Peripheral blood mononuclear cells and lymph nodes of EAN and the changes of OX40 and OX40L under the influence of Rho-kinase inhibitor, we explored the roles of OX40/OX40L in EAN/GBS process and the molecular mechanism of Rho-kinase inhibitor.
Methods 54 female Lewis rats was immunized with the component of Synthetic PNS myelin sheath protein P2 53-78aa and Freund's complete adjuvant, and Rho-kinase inhibitor Fasudil(25mg/kg.d) were injected intraperitoneally daily from 2 days before antigen immunization. The clinical signs of rats and the histopathology were evaluated. The rats were sacrificed at 9days, 17days, 26days after immunized.Ox40 and OX40L mRNA was detected by RT-PCR which come from spleens, sciatic nerves, peripheral blood mononuclear cells and lymphonodes.
Results The peak of clinical course come on 17d p.i in EAN, the mRNA expression of OX40/OX40L was higher on 9d and 17d than 26d.p.i(p<0.05),there was significance difference between the EAN group and CFA control group at the three time point(P<0.05);The demyelination and inflammation cells infiltrating was ameliorated in spinal nerve,The clinical scores in fasudil-treatment group was decereased significantly compared with EAN group(p<0.01);The mRNA expression of OX40 and OX40L in fasudil-treatment group was lower than EAN group at the three time point(p<0.05).CFA group didn't show any clinical manifestation.
Conclusions OX40 and OX40L may play a role in the pathogenesis of EAN by taking part in inducing and effect stage. Rho-kinase inhibitor may ameliorate the development of EAN through inhabiting the OX40 and OX40L activation.
方法:54只Lewis大鼠随机分为EAN模型组(n=6,6,6),EAN+ROK抑制剂干预组(n=6,6,6),完全弗氏佐剂对照组(CFA)组(n=6,6,6)。EAN组大鼠用合成肽段P2 53-78aa+CFA+NS免疫,EAN+ROK抑制剂组从模型制作前两天腹腔注射法舒地尔注射液(25mg/kg.d)治疗。观察各组大鼠发病情况和组织病理学改变。分别在第9天、17天、26天处死动物取其坐骨神经根、脾脏、外周血单个核细胞和淋巴结,采用RT-PCR技术检测OX40和OX40LmRNA在各组织的表达水平。
结果:EAN组大鼠在抗原免疫后第17天达到发病高峰,OX40和OX40L mRNA在第9天(发病早期)和第17天时表达均较高,与第26天相比有显著差异(p＜0.05),各时间点与对照组相比有显著差异(p＜0.05);EAN+ROK抑制剂组大鼠与EAN组相比,其平均最高临床评分明显降低(p＜0.01),坐骨神经炎性细胞浸润和脱髓鞘减轻,OX40和OX40L在各时间点的表达减少(p＜0.05)。CFA组大鼠无症状。
结论:OX40/0X40L可能与EAN发病有关;ROK抑制剂可以减轻EAN发病程度,抑制OX40/0X40L的表达可能是其作用机制之一。
Objective Guillain-Barre Syndrome(GBS) is an autoimmune disease of the peripheral nervous system, characterized by multifocal demyelination and inflammation cells infiltration in peripheral nerves and spinal nerve roots._Experimental allergic neuritis(EAN) is a classical animal model to study pathogenetis of GBS. The activation of peripheral nervous myelin antigen specific CD4~+T cell play key roles in the development of EAN. OX40/OX40L is a new co-stimulatory molecules, it appears to be particularly important for regulating the extent of CD4~+ T cell expansion in the primary T cell respons. Rho/ROK plays an important role in various pathological processes, promoting the migration of T cells, inducing the secretion of inflammatory factors, and triggering cell apoptosis and synapse disintegration. Rho-kinase inhibitors may ameliorate the symptoms in many inflammatory diseases. In this study, through observing the expression of mRNA of OX40 and OX40L in the sciatic nerve, spleen, Peripheral blood mononuclear cells and lymph nodes of EAN and the changes of OX40 and OX40L under the influence of Rho-kinase inhibitor, we explored the roles of OX40/OX40L in EAN/GBS process and the molecular mechanism of Rho-kinase inhibitor.
Methods 54 female Lewis rats was immunized with the component of Synthetic PNS myelin sheath protein P2 53-78aa and Freund's complete adjuvant, and Rho-kinase inhibitor Fasudil(25mg/kg.d) were injected intraperitoneally daily from 2 days before antigen immunization. The clinical signs of rats and the histopathology were evaluated. The rats were sacrificed at 9days, 17days, 26days after immunized.Ox40 and OX40L mRNA was detected by RT-PCR which come from spleens, sciatic nerves, peripheral blood mononuclear cells and lymphonodes.
Results The peak of clinical course come on 17d p.i in EAN, the mRNA expression of OX40/OX40L was higher on 9d and 17d than 26d.p.i(p<0.05),there was significance difference between the EAN group and CFA control group at the three time point(P<0.05);The demyelination and inflammation cells infiltrating was ameliorated in spinal nerve,The clinical scores in fasudil-treatment group was decereased significantly compared with EAN group(p<0.01);The mRNA expression of OX40 and OX40L in fasudil-treatment group was lower than EAN group at the three time point(p<0.05).CFA group didn't show any clinical manifestation.
Conclusions OX40 and OX40L may play a role in the pathogenesis of EAN by taking part in inducing and effect stage. Rho-kinase inhibitor may ameliorate the development of EAN through inhabiting the OX40 and OX40L activation.
引文
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