Vascular endothelial activation, marked by de novo expression of
E-selectin, is an early and essential event in the process of leukocyte extravasation and
inflammation. Evidence suggests that
hepatocyte growth factor (HGF) ameliorates
inflammation in animal models of renal disease, implying that HGF might inhibit specific components of the inflammatory response. This study examined the effect of HGF on endothelial
E-selectin expression in acute
inflammation induced by
tumor necrosis factor (
TNF)-alpha. In vitro, HGF suppressed
TNF-alpha-induced cell surface expression of
E-selectin in human umbilical vein endothelial cells (HUVEC) and inhibited
E-selectin mediated monocytic adhesion to endothelial monolayers. HGF activated
phosphatidylinositol 3-kinase (PI3K)-Akt that in turn inhibited its downstream transducer
glycogen synthase kinase (GSK)3. Blockade of the PI3K-Akt pathway with specific inhibitors abrogated HGF induced inhibitory phosphorylation of GSK3 and suppression of
E-selectin. In addition, selective inhibition of GSK3 activity by
lithium suppressed
TNF-alpha-induced
E-selectin expression and monocytic adhesion, reminiscent of the action of HGF. Moreover, ectopic expression of an uninhibitable mutant
GSK3beta, in which the regulatory serine-9 is replaced by
alanine, abolished HGF's suppressive effect on endothelial
E-selectin. In vivo, administration of exogenous HGF reduced endothelial expression of
E-selectin induced by bolus injection of
TNF-alpha. This was associated with less sequestration of circulating fluorescence-labeled macrophages in the kidney. These findings suggest that HGF ameliorates acute renal
inflammation in part by downregulating
E-selectin mediated macrophage adhesion to the inflamed endothelium.