Hepatocyte growth factor suppresses acute renal inflammation by inhibition of endothelial E-selectin.
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.
Gong
R
R
Department of Medicine, Division of Renal Diseases, Brown University School of Medicine, Providence, Rhode Island 02903, USA. Rujun_Gong@Brown.edu
Rifai
A
A
Dworkin
L D
LD
D000208:Acute Disease; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D019040:E-Selectin / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D008264:Macrophages / Q000502:physiology; D009000:Monocytes; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014471:Umbilical Veins
D019040:E-Selectin; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3