Presence of a mobilizable intracellular pool of hepatocyte growth factor in human polymorphonuclear neutrophils

• Published in: Blood Vol. 99; no. 8; pp. 2997 - 3004
• Main Authors: Grenier, Alain, Chollet-Martin, Sylvie, Crestani, Bruno, Delarche, Charlotte, El Benna, Jamel, Boutten, Anne, Andrieu, Valérie, Durand, Geneviève, Gougerot-Pocidalo, Marie-Anne, Aubier, Michel, Dehoux, Monique
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.04.2002; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Biological Transport; Bone Marrow Cells - chemistry; Bone Marrow Cells - cytology; Cell Compartmentation; Cell Degranulation - drug effects; Cell Degranulation - physiology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gelatinases - analysis; Glycosaminoglycans - metabolism; Hepatocyte Growth Factor - biosynthesis; Hepatocyte Growth Factor - metabolism; Humans; Immunobiology; Myeloid cells: ontogeny, maturation, markers, receptors; Neutrophils - enzymology; Neutrophils - metabolism; Neutrophils - ultrastructure; Polynuclears; Protease Inhibitors - pharmacology; Protein Binding; Protein Precursors - analysis; Protein Precursors - metabolism; Secretory Vesicles - chemistry; Secretory Vesicles - enzymology; Fibroblast growth factor; Immune response; Hepatocyte growth factor; Granulocyte; Leukocyte function; Inflammation; Neutrophil; Cicatrization
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V99.8.2997

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-formylmethionyl-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.