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LIVER AND BILIARY TRACT

Selective inactivation of NF-B in the liver using NF-B decoy suppresses CCl₄-induced liver injury and fibrosis

¹First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan; and ²Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan

Submitted 27 April 2007 ; accepted in final form 13 July 2007

Sustained hepatic inflammation induced by various causes can lead to liver fibrosis. Transcription factor NF-B is important in regulating inflammatory responses, especially in macrophages. We presently investigated whether an NF-B decoy, a synthetic oligodeoxynucleotide (ODN) imitating the NF-B binding site, inhibited the inflammatory response after CCl₄ intoxication to prevent CCl₄-induced hepatic injury and fibrosis. The NF-B decoy was introduced into livers by injecting the spleens of mice, using a hemagglutinating virus of Japan (HVJ)-liposome method. ODN was transferred mainly to macrophages in normal or fibrotic livers. Increases in serum transaminases and production of inflammatory cytokines after a single challenge with CCl₄ were inhibited by the NF-B decoy, which suppressed nuclear translocation of NF-B in liver macrophages. Liver fibrosis induced by CCl₄ administration for 8 wk was suppressed by the NF-B decoy, accompanied by diminished mRNA expression for transforming growth factor (TGF)-, procollagen type 1 ₁, and -smooth muscle actin (SMA). In vitro, isolated liver macrophages showed increased DNA binding activity of NF-B and inflammatory cytokine production after hydrogen peroxide treatment; both increases were inhibited significantly by the NF-B decoy. In contrast, NF-B decoy transferred to isolated hepatic stellate cells (HSC) had no effect on their morphological activation or -SMA expression, although the decoy accelerated tumor necrosis factor (TNF)--induced apoptosis in activated HSC. The effect of NF-B decoy suppressing fibrosis probably results mainly from anti-inflammatory effects on liver macrophages, with a possible minor contribution from its direct proapoptotic effect on activated HSC.

HVJ liposome; liver macrophage; oligodeoxynucleotide; hydrogen peroxide