Hepatocyte growth factor exerts its anti-inflammatory action by disrupting nuclear factor-κB 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)-κB 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-κB signaling. HGF did not significantly affect the phosphorylation or degradation of IκBα; it also did not influence the phosphorylation or nuclear translocation of p65 NF-κB. However, HGF prevented p65 NF-κB 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)-3β. Suppression of GSK-3β activity mimicked HGF and abolished RANTES expression, whereas ectopic expression of GSK-3β restored RANTES induction. HGF also induced renal GSK-3β 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-κB signaling and may be a promising therapeutic agent for progressive renal diseases. Copyright © American Society for Investigative Pathology.