The COX-2-derived PGE(2) autocrine contributes to bradykinin-induced matrix metalloproteinase-9 expression and astrocytic migration via STAT3 signaling.
The COX-2-derived PGE(2) autocrine contributes to bradykinin-induced matrix metalloproteinase-9 expression and astrocytic migration via STAT3 signaling.
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DOI：
10.1186/s12964-020-00680-0
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发表时间：
2020-11-23
期刊：
影响因子：
--
通讯作者：
Hsieh HL
中科院分区：
文献类型：
--
作者：
Lee TH;Liu PS;Tsai MM;Chen JL;Wang SJ;Hsieh HL
基质金属蛋白酶-9（MMP-9）在中枢神经系统（CNS）疾病中受到多种促炎介质的上调。越来越多的研究表明，MMP-9表达是多种中枢神经系统疾病（包括中枢神经系统炎症和神经退行性变）的炎症生物标志物。缓激肽（BK）是一种常见的促炎介质，在一些脑损伤和炎症性疾病中升高。BK升高可能对CNS产生有害影响，可能通过MMP-9上调或脑星形胶质细胞中环氧合酶-2（考克斯-2）衍生的前列腺素E2（PGE 2）产生而加重脑炎症。然而，BK诱导的MMP-9表达与脑星形胶质细胞中考克斯-2衍生的PGE 2释放之间的关系尚不清楚。在此，我们使用大鼠脑星形胶质细胞（RBA）研究考克斯-2/PGE 2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印迹分析证实BK通过考克斯-2/PGE 2依赖性途径诱导MMP-9表达。我们的研究结果表明BK激活天然考克斯-2导致PGE 2的产生和释放。随后，PGE 2通过PGE 2受体（EP）介导的c-Src、Jak 2、ERK 1/2诱导MMP-9表达，进而激活信号转导和转录激活因子3（STAT 3）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，BK诱导的MMP-9蛋白表达的一种新的自分泌途径是通过激活STAT 3介导的天然考克斯-2/PGE 2介导的c-Src/Jak 2/ERK级联反应在脑星形胶质细胞。视频摘要
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 E2 (PGE2) production in brain astrocytes. However, the relationship between BK-induced MMP-9 expression and COX-2-derived PGE2 release in brain astrocytes remains unclear. Herein we used rat brain astrocytes (RBA) to investigate the role of the COX-2/PGE2 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/PGE2-dependent pathway. Our results show activation of native COX-2 by BK led to PGE2 production and release. Subsequently, PGE2 induced MMP-9 expression via PGE2 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/PGE2-mediated c-Src/Jak2/ERK cascades in brain astrocytes. Video Abstract
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影响因子：
4.8
作者：
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