Production of plasminogen activator inhibitor-1 by human mast cells and its possible role in asthma
Production of plasminogen activator inhibitor-1 by human mast cells and its possible role in asthma
复制标题
DOI：
10.4049/jimmunol.165.6.3154
复制
发表时间：
2000-09-15
影响因子：
4.4
通讯作者：
Oh, CK
中科院分区：
文献类型：
--
作者：
Cho, SH;Tam, SW;Oh, CK
1 型纤溶酶原激活剂抑制剂 (PAI-1) 在组织重塑中发挥重要作用。 PAI-1 基因由佛波酯和钙离子载体的组合诱导，在我们通过 DNA 微阵列分析的可诱导人类肥大细胞基因中处于最高水平。 PAI-1 由人肥大细胞系 (HMC)-1 和原代培养的人肥大细胞在刺激后分泌，而在任何一组未刺激的细胞中均检测不到 PAI-1。 PAI-1的分泌是由于PAI-1的从头合成而不是预先形成的PAI-1的分泌。PAI-1分泌的功能意义通过用受刺激的HMC-1细胞的上清液完全抑制组织型纤溶酶原激活剂活性来证明。此外，我们能够通过已知的治疗剂调节HMC-1细胞中的PAI-I基因表达，高剂量（1μM）地塞米松诱导PAI-1 mRNA表达，环孢菌素下调PAI-1基因的表达，放线菌酮消除PAI-I mRNA表达，表明PAI-1基因的转录需要早期基因产物（包括转录因子）的从头合成，最后，我们在肺中证明了PAI-I通过双重免疫荧光研究获得哮喘发作患者的肥大细胞。这是第一份证明激活的人类肥大细胞释放大量功能活性 PAI-1 的报告，这些结果表明 PAI-1 在哮喘气道重塑中发挥重要作用，抑制 PAI-1 活性可能代表一种治疗气道重塑的新方法。
The plasminogen activator inhibitor type 1 (PAI-1) has an essential role in tissue remodeling. The PAI-1 gene was induced by a combination of phorbol ester and calcium ionophore at the highest level among the inducible human mast cell genes that we have analyzed on a DNA microarray. PAI-1 was secreted by both a human mast cell line (HMC)-1 and primary cultured human mast cells upon stimulation, whereas PAI-1 was undetectable in either group of unstimulated cells. The secretion of PAI-1 was due to de novo synthesis of PAI-1 rather than secretion of preformed PAI-1, The functional significance of PAI-1 secretion was demonstrated by complete inhibition of tissue-type plasminogen activator activity with supernatants of stimulated HMC-1 cells. Furthermore, we were able to regulate PAI-I gene expression in HMC-1 cells by known therapeutic agents, High-dose (1 muM) dexamethasone induced PAI-1 mRNA expression, Cyclosporin down-regulated the expression of the PAI-1 gene, Cycloheximide abrogated PAI-I mRNA expression, suggesting that transcription of the PAI-1 gene requires de novo synthesis of early gene products, including transcription factors, Finally, we demonstrated PAI-I in lung mast cells from a patient with asthmatic attack by double-immunofluorescence study. This is the first report demonstrating that activated human mast cells release a striking amount of functionally active PAI-1, These results suggest that PAI-1 could play an important role in airway remodeling of asthma, and inhibition of PAI-1 activity could represent a novel therapeutic approach in the management of airway remodeling.