title: Hepatocyte growth factor exerts its anti-inflammatory action by disrupting nuclear factor-kappaB signaling.
abstract: Renal inflammation, characterized by the influx of inflammatory cells, is believed to play a critical role in the initiation and progression of a wide range of chronic kidney diseases. Here, we show that hepatocyte growth factor (HGF) inhibited renal inflammation and proinflammatory chemokine expression by disrupting nuclear factor (NF)-kappaB signaling. In vivo, HGF gene delivery inhibited interstitial infiltration of inflammatory T cells and macrophages, and suppressed expression of both RANTES (regulated on activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 in a mouse model of obstructive nephropathy. In vitro, HGF abolished RANTES induction in human kidney epithelial cells, which was dependent on NF-kappaB signaling. HGF did not significantly affect the phosphorylation or degradation of IkappaBalpha; it also did not influence the phosphorylation or nuclear translocation of p65 NF-kappaB. However, HGF prevented p65 NF-kappaB binding to its cognate cis-acting element in the RANTES promoter. HGF action was dependent on the activation of the phosphoinositide 3-kinase/Akt pathway, which led to the phosphorylation and inactivation of glycogen synthase kinase (GSK)-3beta. Suppression of GSK-3beta activity mimicked HGF and abolished RANTES expression, whereas ectopic expression of GSK-3beta restored RANTES induction. HGF also induced renal GSK-3beta phosphorylation and inactivation after obstructive injury in vivo. These observations suggest that HGF is a potent anti-inflammatory cytokine that inhibits renal inflammation by disrupting NF-kappaB signaling and may be a promising therapeutic agent for progressive renal diseases.
authors.affiliation: Department of Pathology, University of PittsburghSchool of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Myrto
authors.initials: M
authors.lastname: Giannopoulou
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Tan
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wen
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism*; D007674:Kidney Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016328:NF-kappa B; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019892:eIF-2 Kinase; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3