Eosinophil-derived cationic proteins activate the synthesis of remodeling factors by airway epithelial cells
Eosinophil-derived cationic proteins activate the synthesis of remodeling factors by airway epithelial cells
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DOI：
10.4049/jimmunol.177.7.4861
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发表时间：
2006-10-01
影响因子：
4.4
通讯作者：
Pretolani, Marina
中科院分区：
文献类型：
--
作者：
Pegorier, Sophie;Wagner, Lori A.;Pretolani, Marina
嗜酸性阳离子蛋白影响呼吸上皮的几种生物学功能，但它们对气道重塑的直接贡献尚未确定。我们发现，人支气管上皮细胞系BEAS-2B或原代培养的人支气管上皮细胞，正常人支气管上皮细胞，在亚毒性浓度（0.1、0.3和1 μ M）的主要碱性蛋白（MBP）或嗜酸性过氧化物酶（EPO）下孵育，增加了内皮素-1、tgf - α、tgf - β 1、血小板衍生生长因子(PDGF)- β、表皮生长因子受体、金属蛋白酶(MMP)-9、纤维连接蛋白和tenascin的转录。MMP-1基因表达仅在BEAS-2B细胞中下调。在阳离子蛋白诱导的转录效应之后，ELISA检测上清液中内皮素-1和PDGF-AB的释放，Western blot检测细胞裂解物中MMP-1和MMP-9的水平分别下调和上调。细胞刺激与合成多阳离子，聚l -精氨酸，再现一些但不是全部的作用，MBP和EPO。最后，与聚阴离子分子、聚l -谷氨酸或肝素同时孵育细胞，恢复MMP-1基因表达，但不完全抑制MBP和epo诱导的转录效应以及内皮素-1和PDGF-AB的释放，表明阳离子蛋白部分通过其阳离子电荷起作用。我们得出结论，嗜酸性粒细胞衍生的阳离子蛋白能够刺激支气管上皮合成影响结构细胞数量和行为的因子，并改变细胞外基质的组成和周转。
Eosinophil cationic proteins influence several biological functions of the respiratory epithelium, yet their direct contribution to airway remodeling has not been established. We show that incubation of the human bronchial epithelial cell line, BEAS-2B, or primary cultured human bronchial epithelial cells, normal human bronchial epithelial cells, with subeytotoxic concentrations (0.1, 0.3, and 1 mu M) of major basic protein (MBP), or eosinophil peroxidase (EPO), augmented the transcripts of endothelin-1, TGF-alpha, TGF-beta 1, platelet-derived growth factor (PDGF)-beta, epidermal growth factor receptor, metalloproteinase (MMP)-9, fibronectin, and tenascin. A down-regulation of MMP-1 gene expression was observed exclusively in BEAS-2B cells. Cationic protein-induced transcriptional effects were followed by the release of endothelin-1, PDGF-AB in the supernatants by ELISA, and by a down- and up-regulation, respectively, in the levels of MMP-1 and MMP-9 in cell lysates, by Western blot. Cell stimulation with the synthetic polycation, poly-L-arginine, reproduced some but not all effects of MBP and EPO. Finally, simultaneous cell incubation with the polyanion molecules, poly-L-glutamic acid or heparin, restored MMP-1 gene expression but incompletely inhibited MBP- and EPO-induced transcriptional effects as well as endothelin-1 and PDGF-AB release, suggesting that cationic proteins act partially through their cationic charge. We conclude that eosinophil-derived cationic proteins are able to stimulate bronchial epithelium to synthesize factors that influence the number and behavior of structural cells and modify extracellular matrix composition and turnover.