The effects of endothelin-1 on degranulation, cytokine and growth factor production by skin-derived mast cells.

内皮素-1(ET-1)最初被认为是一种血管收缩因子，现在被认为参与了多种疾病的发病机制，包括血管疾病、炎症性疾病和纤维化疾病。最近的研究表明，肥大细胞也参与了同样的病理条件。在这项研究中，我们使用胎儿皮肤来源的培养的肥大细胞(FSMC)和骨髓来源的培养的肥大细胞(BMMC)来验证ET-1会影响肥大细胞功能并导致此类疾病的假设。FSMC在mRNA和蛋白水平表达ET受体(ET_A和ET_B)，BMMC表达较低水平的ET_A，仅表达少量ET_B。ET-1通过ET_A介导的途径诱导FSMC脱颗粒，但不通过BMMC。不同浓度的ET-1对IgE结合的FSMC脱颗粒有交互作用。ET-1可诱导系膜细胞产生肿瘤坏死因子α和IL-6，但不能促进系膜细胞产生血管内皮生长因子和转化生长因子-β1mRNA。最后，ET-1是由FSMC产生的，而不是由BMMC对Toll样受体配体反应产生的。这些结果表明，ET-1对不同的肥大细胞群的影响截然不同。我们认为，在一定条件下，ET-1可能通过对肥大细胞的多功能作用而参与多种疾病的病理状态。

Endothelin-1 (ET-1), originally described as a vasoconstrictor, is now known to be involved in pathogenesis of various disorders including vascular, inflammatory, and fibrotic diseases. Recent studies suggest that mast cells are also involved in the same pathological conditions. In this study, we tested a hypothesis that ET-1 would affect mast cell functions and contribute to such disease conditions, using fetal skin-derived cultured mast cells (FSMC) and bone marrow-derived cultured cultured mast cells (BMMC). FSMC expressed ET receptors (ET_A and ET_B) at mRNA and protein levels, BMMC expressed lower levels of ET_A, and little, if any, ET_B. ET-1 induced degranulation by FSMC, but not by BMMC thorough ET_A-mediated pathways. ET-1 at different concentrations exerted the reciprocal effects on degranulation by IgE-bound FSMC. Furthermore, ET-1 induced TNFα and IL-6 production by FSMC, but not by BMMC, and significantly enhanced VEGF production and TGF-β1 mRNA expression by FSMC. Finally, ET-1 was produced by FSMC, but not by BMMC in response to Toll-like receptor ligands. These results indicate contrasting impacts of ET-1 on distinct mast cell populations. We propose that ET-1 may participate in pathological conditions of various disorders via its multi-functional effects on mast cells under certain conditions.