Anti-monocyte chemoattractant protein-1 gene therapy prevents dimethylnitrosamine-induced hepatic fibrosis in rats.
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. 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. 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 alpha-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. In conclusion, 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.
Tsuruta
Satoru
S
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nakamuta
Makoto
M
Enjoji
Munechika
M
Kotoh
Kazuhiro
K
Hiasa
Kenichi
K
Egashira
Kensuke
K
Nawata
Hajime
H
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D003062:Codon / Q000235:genetics* / Q000627:therapeutic use*; D004121:Dimethyl Sulfoxide; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000628:therapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003062:Codon; D004121:Dimethyl Sulfoxide