Hepatocyte growth factor exerts its anti-inflammatory action by disrupting nuclear factor-kappa B signaling

作者：Giannopoulou Myrto; Dai Chunsun; Tan Xiaoyue; Wen Xiaoyan; Michalopoulos George K; Liu Youhua^*

来源：American Journal Of Pathology, 2008, 173(1): 30-41.

DOI：10.2353/ajpath.2008.070583

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)-kappa 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-kappa B signaling. HGF did not significantly affect the phosphorylation or degradation of I kappa B alpha; it also did not influence the phosphorylation or nuclear translocation of p65 NF-kappa B. However, HGF prevented p65 NF-kappa 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)-3 beta. Suppression of GSK-3 beta activity mimicked HGF and abolished RANTES expression, whereas ectopic expression of GSK-3 beta restored RANTES induction. HGF also induced renal GSK-3 beta 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-kappa B signaling and may be a promising therapeutic agent for progressive renal diseases.

• 出版日期2008-7