Stroke Center and Stroke Section, Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Department of Microbiology, Soochow University, Taipei, Taiwan.
Cell Commun Signal. 2020 Nov 23;18(1):185. doi: 10.1186/s12964-020-00680-0.
The matrix metalloproteinase-9 (MMP-9) is up-regulated by several proinflammatory mediators in the central nervous system (CNS) diseases. Increasing reports show that MMP-9 expression is an inflammatory biomarker of several CNS disorders, including the CNS inflammation and neurodegeneration. Bradykinin (BK) is a common proinflammatory mediator and elevated in several brain injury and inflammatory disorders. The raised BK may be detrimental effects on the CNS that may aggravate brain inflammation through MMP-9 up-regulation or cyclooxygenase-2 (COX-2)-derived prostaglandin E (PGE) production in brain astrocytes. However, the relationship between BK-induced MMP-9 expression and COX-2-derived PGE release in brain astrocytes remains unclear.
Herein we used rat brain astrocytes (RBA) to investigate the role of the COX-2/PGE system in BK-induced MMP-9 expression. We used zymographic, RT-PCR, EIA, and Western blotting analyses to confirm that BK induces MMP-9 expression via a COX-2/PGE-dependent pathway.
Our results show activation of native COX-2 by BK led to PGE production and release. Subsequently, PGE induced MMP-9 expression via PGE receptor (EP)-mediated c-Src, Jak2, ERK1/2, and then activated signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, up-regulation of MMP-9 by BK via the pathway may promote astrocytic migration.
These results demonstrated that a novel autocrine pathway for BK-induced MMP-9 protein expression is mediated through activation of STAT3 by native COX-2/PGE-mediated c-Src/Jak2/ERK cascades in brain astrocytes. Video Abstract.
基质金属蛋白酶-9（MMP-9）在中枢神经系统（CNS）疾病中被几种促炎介质上调。越来越多的报道表明，MMP-9 表达是几种 CNS 疾病的炎症生物标志物，包括 CNS 炎症和神经退行性变。缓激肽（BK）是一种常见的促炎介质，在几种脑损伤和炎症性疾病中升高。升高的 BK 可能对 CNS 产生有害影响，通过 MMP-9 上调或脑星形胶质细胞中环氧化酶-2（COX-2）衍生的前列腺素 E（PGE）产生加重脑炎症。然而，BK 诱导的 MMP-9 表达与 COX-2 衍生的 PGE 释放之间的关系在脑星形胶质细胞中仍不清楚。
本文采用大鼠脑星形胶质细胞（RBA）研究 COX-2/PGE 系统在 BK 诱导的 MMP-9 表达中的作用。我们使用酶谱、RT-PCR、EIA 和 Western blot 分析来证实 BK 通过 COX-2/PGE 依赖性途径诱导 MMP-9 表达。
我们的结果表明，BK 激活天然 COX-2 导致 PGE 的产生和释放。随后，PGE 通过 PGE 受体（EP）介导的 c-Src、Jak2、ERK1/2 诱导 MMP-9 表达，进而激活信号转导子和转录激活子 3（STAT3）信号通路。最后，BK 通过该途径上调 MMP-9 可能促进星形胶质细胞迁移。
这些结果表明，一种新的内源性途径，通过天然 COX-2/PGE 介导的 c-Src/Jak2/ERK 级联激活 STAT3，介导 BK 诱导的 MMP-9 蛋白表达，在脑星形胶质细胞中。视频摘要。
