Anti-monocyte Chemoattractant Protein-1 Gene Therapy Prevents Dimethylnitrosamine-induced Hepatic Fibrosis in Rats

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Background: Monocyte Chemoattractant Protein-1 (MCP-1) has been implicated in the process of hepatic inflammation, recruiting monocytes and lymphocytes during liver injury. MCP-1 also activates directly hepatic stellate cells, which play a major role in hepatic fibrosis. However, it remains unclear whether blockage of MCP-1 signaling could prevent hepatic fibrosis in vivo.Methods: We evaluated a strategy for anti-MCP-1 gene therapy against hepatic fibrosis by transfecting an amino-terminal deletion mutant, lacking the amino-terminal codons 2 to 8 of the human MCP-1 gene and designated 7ND, into skeletal muscle in a rat experimental model of dimethylnitrosamine (DMN) induced fibrosis.Results: Anti-MCP-1 gene therapy decreased significantly the occurrence of DMN-induced hepatic fibrosis evaluated by computed image analysis and by measurement of hydroxyproline contents of the liver, accompanied by a reduction in the expressions of α-smooth muscle actin. This treatment also caused a significant decrease in hepatic tissue levels of interleukin- (IL-) 12 (Th1 cytokine) and an increase in those of IL-10 (Th2 cytokine), indicating a change in the TH1/Th2 cytokine balance in the liver.Conclusions: Blockade of MCP-1 after intramuscular transfer of the 7ND gene suppressed hepatic fibrosis, and this strategy may be a useful and feasible gene therapy against hepatic fibrosis.