Hepatocyte growth factor is a potent trigger of neutrophil adhesion through rapid activation of lymphocyte function-associated antigen-1.
Recruitment of neutrophils into tissue occurs in several pathologic processes such as inflammation, atherosclerosis, thrombosis, and ischemia. In inflammation, the adherence of neutrophils to the endothelium depends on neutrophil integrins. Integrin-mediated adhesion is tightly regulated, ie, integrins do not function if neutrophils are not triggered by certain activation stimuli. We investigated the role of hepatocyte growth factor (HGF) in the adhesion of neutrophils to endothelial cells in inflammation. Our results showed that (a) HGF induced not only lymphocyte function-associated antigen-1 (LFA-1)-mediated adhesion of neutrophils to endothelial cells but also transmigration of neutrophils in a concentration-dependent manner; (b) HGF functionally transformed neutrophil integrin LFA-1 to active form and reduced surface L-selectin expression level; (c) HGF induced F-actin polymerization and cytoskeletal rearrangement within seconds; (d) genistein, a tyrosine kinase inhibitor, as well as wortmannin, a phosphoinositide 3 (PI 3)-kinase inhibitor, inhibited both F-actin polymerization and LFA-1-mediated adhesion of neutrophils to endothelial cells; and (e) neutrophils in cutaneous inflamed tissue highly expressed HGF and serum levels of HGF were elevated in patients with Behçet's disease, which is associated with neutrophilic vasculitis and marked neutrophil accumulation. Our results indicate that HGF plays a pivotal role in integrin-mediated adhesion and transmigration of neutrophils to sites of acute inflammation through cytoskeletal rearrangement activated by tyrosine kinase and PI 3-kinase signaling.
Mine
S
S
The First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Tanaka
Y
Y
Suematu
M
M
Aso
M
M
Fujisaki
T
T
Yamada
S
S
Eto
S
S
D000199:Actins / Q000502:physiology; D000730:Androstadienes / Q000494:pharmacology; D001528:Behcet Syndrome / Q000097:blood; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D019041:L-Selectin / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D011108:Polymers / Q000378:metabolism; D013997:Time Factors; D000077191:Wortmannin
D000199:Actins; D000730:Androstadienes; D004791:Enzyme Inhibitors; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D011108:Polymers; D019041:L-Selectin; D017228:Hepatocyte Growth Factor; D019833:Genistein; D000077191:Wortmannin