Hepatocyte Growth Factor Exerts Its Anti-Inflammatory Action by Disrupting Nuclear Factor-κB Signaling

• DOI: 10.2353/ajpath.2008.070583
• Publication Date: 2008-05-24T00:53:54Z
• Authors: Myrto Giannopoulou; Chunsun Dai; Xiaoyue Tan; Xiaoyan Wen; George K. Michalo...; Youhua Liu
• Keywords: Inflammation; Hepatocyte Growth Factor; Blotting, Western; Gene Transfer Techniques; Fluorescent Antibody Technique; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Monocytes; I-kappa B Kinase; 3. Good health; Enzyme Activation; Chemotaxis, Leukocyte; Glycogen Synthase Kinase 3; Mice; 03 medical and health sciences; 0302 clinical medicine; Animals; Humans; Immunoprecipitation; Kidney Diseases; Chemokine CCL5; Cells, Cultured; Chemokine CCL2

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.