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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/G631    most recent 00185.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Son, G. Articles by Fujimoto, J. Search for Related Content PubMed PubMed Citation Articles by Son, G. Articles by Fujimoto, J.

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