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 pr ocesses such as inflammation, atherosclerosis, thrombosis, and ischemi a. In inflammation, the adherence of neutrophils to the endothelium de pends on neutrophil integrins. Integrin-mediated adhesion is tightly r egulated, ie, integrins do not function if neutrophils are not trigger ed by certain activation stimuli. We investigated the role of hepatocy te growth factor (HGF) in the adhesion of neutrophils to endothelial c ells 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 neutrophi ls in a concentration-dependent manner; (b) HGF functionally transform ed neutrophil integrin LFA-1 to active form and reduced surface L-sele ctin expression level; (c) HGF induced F-actin polymerization and cyto skeletal rearrangement within seconds; (d) genistein, a tyrosine kinas e inhibitor, as well as wortmannin, a phosphoinositide 3 (PI 3)-kinase inhibitor, inhibited both F-actin polymerization and LFA-1-mediated a dhesion of neutrophils to endothelial cells; and (e) neutrophils in cu taneous inflamed tissue highly expressed HGF and serum levels of HGF w ere elevated in patients with Behcet's disease, which is associated wi th neutrophilic vasculitis and marked neutrophil accumulation. Our res ults indicate that HGF plays a pivotal role in integrin-mediated adhes ion and transmigration of neutrophils to sites of acute inflammation t hrough cytoskeletal rearrangement activated by tyrosine kinase and Pf 3-kinase signaling.