Chen Zhiguo, Duan Rui-Sheng, Concha Q Hernan, Wu Qinyang, Mix Eilhard, Winblad Bengt, Ljunggren Hans-Gustaf, Zhu Jie
Division of Experimental Geriatrics, Department of Neurotec, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Neurobiol Dis. 2004 Nov;17(2):171-8. doi: 10.1016/j.nbd.2004.07.018.
The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this issue, we used the model of kainic acid (KA)-induced hippocampal injury in IL-12p35 knockout (KO) mice, a well-characterized model for human neurodegenerative diseases. After KA treatment, hippocampal neurodegeneration was significantly less severe in the IL-12p35 KO mice than in wild-type mice as demonstrated by reduced pathological changes and astrogliosis. One day after KA treatment, levels of F4/80 and CD86 expression on microglia were significantly lower in IL-12p35 KO mice than in wild-type mice analyzed by flow cytometry, indicating that IL-12p35 deficiency resulted in lower levels of microglial activation. Five days after KA treatment, CD86 expression on microglia of wild-type mice was still higher, whereas F4/80 expression in wild-type mice decreased and was similar to that in IL-12p35 KO mice. Because microglial activation is necessary for KA-induced neurodegeneration, the lower level of microglial activation in the absence of IL-12p35 may alleviate hippocampal injury in KO mice. In summary, this study indicates that IL-12 may play a critical role in excitotoxin-induced brain injury.
白细胞介素-12（IL-12）在大脑兴奋性毒性神经退行性变中的作用在很大程度上尚不清楚。为了解决这个问题，我们使用了红藻氨酸（KA）诱导的白细胞介素-12p35基因敲除（KO）小鼠海马损伤模型，这是一种用于人类神经退行性疾病的特征明确的模型。KA处理后，与野生型小鼠相比，IL-12p35 KO小鼠海马神经退行性变明显较轻，病理变化和星形胶质细胞增生减少证明了这一点。KA处理一天后，通过流式细胞术分析，IL-12p35 KO小鼠小胶质细胞上F4/80和CD86的表达水平明显低于野生型小鼠，表明IL-12p35缺乏导致小胶质细胞活化水平降低。KA处理五天后，野生型小鼠小胶质细胞上CD86的表达仍然较高，而野生型小鼠中F4/80的表达下降，与IL-12p35 KO小鼠相似。由于小胶质细胞活化是KA诱导神经退行性变所必需的，缺乏IL-12p35时小胶质细胞活化水平较低可能减轻KO小鼠的海马损伤。总之，本研究表明IL-12可能在兴奋性毒素诱导的脑损伤中起关键作用。
