Zhang Xing-Mei, Duan Rui-Sheng, Chen Zhiguo, Quezada Hernan Concha, Mix Eilhard, Winblad Bengt, Zhu Jie
Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital in Huddinge, Stockholm, Sweden.
Exp Neurol. 2007 May;205(1):64-73. doi: 10.1016/j.expneurol.2007.01.019. Epub 2007 Jan 25.
The role of interleukin-18 (IL-18) in excitotoxic neurodegeneration is largely unknown. To address this issue, we used kainic acid (KA)-induced hippocampal neurodegeneration in IL-18 knockout (KO) mice. One day after KA administration, clinical symptoms and histopathological changes did not differ between IL-18 KO mice and wild-type mice. However, 7 days after KA application the hippocampal neurodegeneration was markedly severe in IL-18 KO mice as demonstrated by increased locomotion and prominent histopathological changes including neuronal cell loss, microglia activation and astrogliosis. Surprisingly, when wild-type mice received recombinant mouse IL-18 (rmIL-18) in advance, after KA treatment both the clinical and pathological signs were dose-dependently aggravated compared to mice without rmIL-18 pre-treatment. To clarify the mechanism behind this, we assessed the expression of the IL-18 associated cytokines IL-12, IL-1beta, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus by immunohistochemistry and flow cytometry. IL-12 and IFN-gamma expression was strongly increased in IL-18 KO mice when compared to wild-type mice 7 days after KA treatment in agreement with increased microglia activation. These results suggest that the role of IL-18 in excitotoxic injury in IL-18 deficient mice may be overcompensated by increased IL-12 secretion.
白细胞介素-18（IL-18）在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，我们在IL-18基因敲除（KO）小鼠中使用海藻酸（KA）诱导海马神经退行性变。给予KA一天后，IL-18 KO小鼠和野生型小鼠的临床症状和组织病理学变化没有差异。然而，在应用KA 7天后，IL-18 KO小鼠的海马神经退行性变明显更严重，表现为活动增加以及包括神经元细胞丢失、小胶质细胞活化和星形胶质细胞增生在内的显著组织病理学变化。令人惊讶的是，当野生型小鼠预先接受重组小鼠IL-18（rmIL-18）时，与未进行rmIL-18预处理的小鼠相比，KA处理后临床和病理体征均呈剂量依赖性加重。为了阐明其背后的机制，我们通过免疫组织化学和流式细胞术评估了海马中与IL-18相关的细胞因子IL-12、IL-1β、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）的表达。与野生型小鼠相比，在KA处理7天后，IL-18 KO小鼠中IL-12和IFN-γ的表达显著增加，这与小胶质细胞活化增加一致。这些结果表明，在IL-18缺陷小鼠中，IL-18在兴奋性毒性损伤中的作用可能被IL-12分泌增加所过度补偿。
