Published online before print May 23, 2008

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(American Journal of Pathology. 2008;173:30-41.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070583

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

From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

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)-B 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-B signaling. HGF did not significantly affect the phosphorylation or degradation of IB; it also did not influence the phosphorylation or nuclear translocation of p65 NF-B. However, HGF prevented p65 NF-B 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-B signaling and may be a promising therapeutic agent for progressive renal diseases.

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