Allan S M
School of Biological Sciences, 1.124 Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
Ann N Y Acad Sci. 2000;917:84-93. doi: 10.1111/j.1749-6632.2000.tb05373.x.
Experimental and clinical damage to the brain leads to rapid upregulation of an array of cytokines predominantly by glia. These cytokines may exert neurotoxic or neuroprotective actions. This paper will focus on the pro-inflammatory cytokine interleukin-1 (IL-1), which participates in diverse forms of brain damage including ischemia, brain trauma, and excitotoxic injury. Administration of low doses of IL-1 markedly exacerbates these forms of brain damage, whereas blocking IL-1 release or actions reduces neuronal death. IL-1 receptor antagonist (IL-1ra) is also upregulated by brain damage (mainly by neurons) and acts as an endogenous inhibitor of neurodegeneration, presumably by blocking IL-1 actions on its receptor. We have studied the actions of both IL-1 and IL-1ra in experimental models of ischemic and neurotoxic injury in rats, and have found site-specific effects within the striatum. On the basis of this and further work, we propose that IL-1 can exacerbate cell death in these conditions by modifying polysynaptic anterograde pathways leading from the striatum to the cortex. The precise nature of these pathways remains undetermined, as do the underlying mechanisms by which IL-1 can exert its effects, but appear to involve induction of IL-1 in specific brain regions and activation of cortical glutamatergic pathways.
对大脑的实验性和临床损伤会导致一系列细胞因子迅速上调，主要由神经胶质细胞产生。这些细胞因子可能发挥神经毒性或神经保护作用。本文将聚焦于促炎细胞因子白细胞介素-1（IL-1），它参与多种形式的脑损伤，包括缺血、脑外伤和兴奋性毒性损伤。给予低剂量的IL-1会显著加剧这些形式的脑损伤，而阻断IL-1的释放或作用则可减少神经元死亡。IL-1受体拮抗剂（IL-1ra）也会因脑损伤（主要由神经元产生）而上调，并作为神经退行性变的内源性抑制剂，可能是通过阻断IL-1对其受体的作用。我们在大鼠缺血和神经毒性损伤的实验模型中研究了IL-1和IL-1ra的作用，并在纹状体内发现了位点特异性效应。基于此及进一步的研究工作，我们提出，在这些情况下，IL-1可通过改变从纹状体到皮质的多突触顺行通路来加剧细胞死亡。这些通路的确切性质仍未确定，IL-1发挥其作用的潜在机制也不清楚，但似乎涉及特定脑区中IL-1的诱导以及皮质谷氨酸能通路的激活。
