Laboratoire de Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique, Université de Bourgogne, Dijon F-21000, France.
Endocrinology. 2012 Jun;153(6):2568-75. doi: 10.1210/en.2012-1137. Epub 2012 Apr 16.
Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination. However, the components of this inflammatory process in P-NALD remain elusive. In this study, we used transcriptomic profiling and PCR array analyses to explore inflammatory gene expression in patient fibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed to very-long-chain fatty acids exhibited increased mRNA expression of IL-1α and IL-1β cytokines. Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated by MAPK, p38MAPK, and Jun N-terminal kinase inhibitors. Thus, the absence of acyl-coenzyme A oxidase 1 activity in P-NALD fibroblasts triggers an inflammatory process, in which the IL-1 pathway seems to be central. The use of specific kinase inhibitors may permit the modulation of the enhanced inflammatory status.
在几种过氧化物酶体神经退行性疾病中，假性新生儿肾上腺脑白质营养不良（P-NALD）的特征是酰基辅酶 A 氧化酶 1（ACOX1）缺乏，导致极长链脂肪酸（VLCFA）和炎症性脱髓鞘的积累。然而，P-NALD 中这种炎症过程的组成部分仍不清楚。在这项研究中，我们使用转录组谱分析和 PCR 阵列分析来探索患者成纤维细胞中的炎症基因表达。我们的结果表明，IL-1 炎症途径的激活伴随着两种 IL-1 靶基因，IL-6 和 IL-8 细胞因子的分泌增加。暴露于极长链脂肪酸的人成纤维细胞表现出 IL-1α 和 IL-1β 细胞因子的 mRNA 表达增加。此外，患者成纤维细胞中 IL-6 和 IL-8 细胞因子的表达可被 MAPK、p38MAPK 和 Jun N-末端激酶抑制剂下调。因此，P-NALD 成纤维细胞中酰基辅酶 A 氧化酶 1 活性的缺失会引发炎症过程，其中 IL-1 途径似乎是中心环节。使用特定的激酶抑制剂可能允许调节增强的炎症状态。
