Presence of a mobilizable intracellular pool of hepatocyte growth factor in human polymorphonuclear neutrophils.
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.
Grenier
Alain
A
Laboratoire de Biochimie, Hôpital de Montfermeil, Montfermeil, France.
Chollet-Martin
Sylvie
S
Crestani
Bruno
B
Delarche
Charlotte
C
El Benna
Jamel
J
Boutten
Anne
A
Andrieu
Valérie
V
Durand
Geneviève
G
Gougerot-Pocidalo
Marie-Anne
MA
Aubier
Michel
M
Dehoux
Monique
M
D001692:Biological Transport; D001854:Bone Marrow Cells / Q000737:chemistry / Q000166:cytology; D002451:Cell Compartmentation; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology; D018093:Gelatinases / Q000032:analysis; D006025:Glycosaminoglycans / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D011498:Protein Precursors / Q000032:analysis / Q000378:metabolism; D022142:Secretory Vesicles / Q000737:chemistry / Q000201:enzymology
D006025:Glycosaminoglycans; D011480:Protease Inhibitors; D011498:Protein Precursors; D017228:Hepatocyte Growth Factor; D018093:Gelatinases