Presence of a mobilizable intracellular pool of hepatocyte growth factor in human polymorphonuclear neutrophils
Presence of a mobilizable intracellular pool of hepatocyte growth factor in human polymorphonuclear neutrophils
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DOI：
10.1182/blood.v99.8.2997
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发表时间：
2002-04-15
期刊：
影响因子：
20.3
通讯作者：
Dehoux, M
中科院分区：
文献类型：
--
作者：
Grenier, A;Chollet-Martin, S;Dehoux, M
肝细胞生长因子 (HGF) 是一种肝素结合因子，作为单链无活性前体 (pro-HGF) 合成，通过蛋白水解转化为活性异二聚体（成熟 HGF）。 HGF 具有多效活性，并参与上皮细胞和内皮细胞有丝分裂发生、运动发生和形态发生的调节。由于多形核中性粒细胞 (PMN) 分泌大量参与调节局部炎症的细胞因子，我们研究了它们产生 HGF 的能力。我们发现 HGF 储存在分泌囊泡和明胶酶/特定颗粒中。当用佛波醇肉豆蔻酸酯乙酸酯或 N-甲酰基亚甲基-亮氨酰-苯丙氨酸刺激中性粒细胞时，这种细胞内储备通过脱颗粒而迅速动员。放线菌酮不影响HGF的释放。此外，在骨髓髓样细胞中发现了 HGF 信使 RNA 和蛋白质表达，表明 HGF 合成可能发生在 PMN 成熟过程中。在成熟的循环PMN中，细胞内HGF是前HGF形式，而脱颗粒分泌的HGF是成熟形式。此外，用氟磷酸二异丙酯预处理的 PMN 仅释放前 HGF 形式，表明 PMN 衍生的丝氨酸蛋白酶参与蛋白水解过程。我们还获得了分泌的成熟 HGF 结合 PMN 衍生的糖胺聚糖（可能是硫酸乙酰肝素）的证据。这些发现表明，浸润受损组织的 PMN 可能通过产生 HGF（组织再生的主要介质）来调节局部伤口愈合和修复。 （血液。2002；99：2997-3004）。 (C) 2002 年，美国血液学会。
Hepatocyte growth factor (HGF), a heparin-binding factor, is synthesized as a single-chain inactive precursor (pro-HGF), which is converted by proteolysis to an active heterodimer (mature HGF). HGF has pleiotropic activities and has been implicated in the regulation of mitogenesis, motogenesis, and morphogenesis of epithelial and endothelial cells. As polymorphonuclear neutrophils (PMNs) secrete numerous cytokines involved in the modulation of local inflammation, we investigated their ability to produce HGF. We found that HGF was stored in secretory vesicles and in gelatinase/specific granules. This intracellular stock was rapidly mobilized by degranulation when neutrophils were stimulated with phorbol myristate acetate or N-formylmethlonyl-leucyl-phenylalanine. Cycloheximide did not affect the release of HGF. Moreover, HGF messenger RNA and protein expression was found in bone marrow myeloid cells, suggesting that HGF synthesis likely occurs during PMN maturation. In mature circulating PMNs, intracellular HGF was in the pro-HGF form, whereas the HGF secreted by degranulation was the mature form. Furthermore, PMNs pretreated with diisopropyl fluorophosphate only released the pro-HGF form, suggesting that PMN-derived serine protease(s) are involved in the proteolytic process. We also obtained evidence that secreted mature HGF binds PMN-derived glycosaminoglycans (probably heparan sulfate). These findings suggest that PMNs infiltrating damaged tissues may modulate local wound healing and repair through the production of HGF, a major mediator of tissue regeneration. (Blood. 2002;99: 2997-3004). (C) 2002 by The American Society of Hematology.