Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
Acta Trop. 2013 Jul;127(1):14-20. doi: 10.1016/j.actatropica.2013.03.004. Epub 2013 Mar 18.
Matrix metalloproteinase (MMP)-2 and MMP-9 can cleave fibronectin, allowing leukocyte migration to the site of Toxoplasma gondii infection during toxoplasmic encephalitis. The aim of this study was to investigate the association between extracellular signal-regulated kinase (Erk)1/2-nuclear factor (NF)-κB pathway and MMP-2/-9 expression in astroglia infected with T. gondii tachyzoite in vitro. Our results showed that phosphorylated (p)-Erk1/2 transiently increased 1h post-infection (PI) and p-NF-κB significantly increased from 1h PI to 12h PI in cell homogenates. NF-κB was bound directly to oligonucleotides containing putative NF-κB binding sites for the MMP-9 promoter. Additionally, expression of p-NF-κB, MMP-2, and MMP-9 was significantly decreased by MG132, an indirect NF-κB inhibitor. Treatment with PD98059, an Erk kinase inhibitor, efficiently reduced p-Erk1/2, p-NF-κB, MMP-2, and MMP-9 expression. These results suggest that suppression of the Erk1/2-NF-κB signaling pathway causes reductions in MMP-2 and MMP-9 activities in astroglia response to T. gondii infection. Thus, inhibiting this signaling intermediate involved in MMP-2 and MMP-9 expression may be a potential method for controlling inflammatory development of T. gondii-induced encephalitis.
基质金属蛋白酶（MMP）-2 和 MMP-9 可以切割纤维连接蛋白，允许白细胞迁移到弓形体脑炎感染部位。本研究旨在探讨细胞外信号调节激酶（Erk）1/2-核因子（NF）-κB 通路与体外感染弓形虫速殖子的星形胶质细胞中 MMP-2/-9 表达之间的关系。我们的结果表明，磷酸化（p）-Erk1/2 在感染后 1 小时（PI）短暂增加，p-NF-κB 从 1 小时 PI 到 12 小时 PI 在细胞匀浆中显著增加。NF-κB 直接与含有 MMP-9 启动子的推定 NF-κB 结合位点的寡核苷酸结合。此外，间接 NF-κB 抑制剂 MG132 可显著降低 p-NF-κB、MMP-2 和 MMP-9 的表达。用 Erk 激酶抑制剂 PD98059 处理可有效降低 p-Erk1/2、p-NF-κB、MMP-2 和 MMP-9 的表达。这些结果表明，抑制 Erk1/2-NF-κB 信号通路可降低星形胶质细胞对弓形虫感染的 MMP-2 和 MMP-9 活性。因此，抑制参与 MMP-2 和 MMP-9 表达的这种信号中间物可能是控制弓形虫诱导的脑炎炎症发展的一种潜在方法。
