Proinflammatory Orientation of the Interleukin 1 System and Downstream Induction of Matrix Metalloproteinase 9 in the Pathophysiology of Human Perinatal White Matter Damage
Proinflammatory Orientation of the Interleukin 1 System and Downstream Induction of Matrix Metalloproteinase 9 in the Pathophysiology of Human Perinatal White Matter Damage
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DOI：
10.1097/nen.0b013e3181f971e4
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发表时间：
2010-11-01
影响因子：
3.2
通讯作者：
Kadhim, Hazim
中科院分区：
文献类型：
--
作者：
Girard, Sylvie;Sebire, Guillaume;Kadhim, Hazim
临床前模型显示白细胞介素1（IL-1）系统在围产期脑损伤的发病机制中的直接作用，但将这些发现与人类白色物质损伤（WMD）联系起来的证据需要在人类病例中得到证实。我们使用免疫组织化学分析了IL-1 β系统，以表征IL-1受体（IL-1 R1和IL-1 R2）、IL-1 R拮抗剂（IL-1 Ra）的表达，以及9例大规模杀伤性武器患者脑中下游效应物的诱导。白细胞介素1 β过表达与IL-1 R1和IL-1 R2免疫反应性与大规模杀伤性武器的地区，免疫标记的星形胶质细胞和小胶质细胞/巨噬细胞。这些受体在同一大脑中未受损的白色物质中没有免疫反应性。白细胞介素-1 Ra的表达明显低于IL-1 β的表达。这种IL-1 β/IL-1 Ra的不平衡在极早产儿与近足月儿的大脑中特别明显。我们还发现了基质金属蛋白酶9（MMP-9）在大规模杀伤性武器领域的过度表达。MMP-9与IL-1 β共定位于受累脑区的小胶质细胞/巨噬细胞中。这些数据表明，有激活和促炎性取向的IL-1系统与下游诱导MMP-9在围产期大规模毁灭性疾病。因为这两种介质都被称为参与神经细胞损伤，我们推断，IL-1通路激活有一个有害的作用，在人类新生儿大规模杀伤性武器的病理生理。
A preclinical model showed a direct role of the interleukin 1 (IL-1) system in the pathogenesis of perinatal brain damage, but evidence linking these findings to human white matter damage (WMD) requires confirmation in human cases. We analyzed the IL-1 beta system using immunohistochemistry to characterize the expression of IL-1 receptors (IL-1R1 and IL-1R2), IL-1R antagonist (IL-1Ra), and induction of downstream effectors in 9 human brains with WMD. Interleukin 1 beta overexpression was associated with IL-1R1 and IL-1R2 immunoreactivity in areas with WMD; immunolabeling for both was detected on astrocytes and microglia/macrophages. There was no immunoreactivity for these receptors in nondamaged white matter in the same brains. Interleukin-1Ra expression was significantly less upregulated than that of IL-1 beta. This IL-1 beta/IL-1Ra imbalance was particularly pronounced in the brains of very preterm versus nearterm infants. We additionally found overexpression of matrix metalloproteinase 9 (MMP-9) in WMD areas. The MMP-9 colocalized with IL-1 beta in microglia/macrophages in affected cerebral areas. These data indicate that there is activation and proinflammatory orientation of the IL-1 system with downstream induction of MMP-9 in perinatal WMD. Because both of these mediators are known to be involved in neural cell injury, we infer that IL-1 pathway activation has a deleterious role in the pathophysiology of WMD in human neonates.