Wiehler Shahina, Cuvelier Susan L, Chakrabarti Subhadeep, Patel Kamala D
Departments of Physiology and Biophysics, University of Calgary, Calgary, Alta., Canada T2N 4N1.
Biochem Biophys Res Commun. 2004 Mar 5;315(2):463-70. doi: 10.1016/j.bbrc.2004.01.078.
Eosinophils constitutively produce and store matrix metalloproteinase-9 (MMP-9), a protease implicated in tissue remodeling observed in asthma. In this study, we examined the rapid release of stored MMP-9 from eosinophils following stimulation with either tumor necrosis factor-alpha (TNF-alpha or the bacterial product fMLP. TNF-alpha induced rapid and robust pro-MMP-9 release from eosinophils. MMP-9 could be detected in the cell-free supernatant as early as 15min after stimulation. Rapid MMP-9 release was similarly induced by fMLP. TNF-alpha stimulation activated the mitogen-activated protein (MAP) kinases p38 MAP kinase and extracellular signal-regulated kinase-2 (Erk-2) at times and concentrations similar to that observed for MMP-9 release. Using pharmacological inhibitors, we found that TNF-alpha-stimulated MMP-9 release was mediated by p38 MAP kinase, but not Erk-1/2. Signaling through p38 MAP kinase may represent a universal mechanism for MMP-9 release from eosinophils, as fMLP-induced MMP-9 release was also regulated by p38 MAP kinase.
嗜酸性粒细胞持续产生并储存基质金属蛋白酶-9（MMP-9），这是一种与哮喘中观察到的组织重塑有关的蛋白酶。在本研究中，我们检测了用肿瘤坏死因子-α（TNF-α）或细菌产物fMLP刺激后嗜酸性粒细胞中储存的MMP-9的快速释放。TNF-α诱导嗜酸性粒细胞快速且大量释放前MMP-9。刺激后15分钟即可在无细胞上清液中检测到MMP-9。fMLP同样能诱导MMP-9快速释放。TNF-α刺激激活丝裂原活化蛋白（MAP）激酶p38 MAP激酶和细胞外信号调节激酶-2（Erk-2）的时间和浓度与观察到的MMP-9释放相似。使用药理学抑制剂，我们发现TNF-α刺激的MMP-9释放是由p38 MAP激酶介导的，而非Erk-1/2。通过p38 MAP激酶的信号传导可能代表嗜酸性粒细胞释放MMP-9的一种普遍机制，因为fMLP诱导的MMP-9释放也受p38 MAP激酶调节。
