title: Selective inactivation of NF-kappaB in the liver using NF-kappaB decoy suppresses CCl4-induced liver injury and fibrosis.
abstract: Sustained hepatic inflammation induced by various causes can lead to liver fibrosis. Transcription factor NF-kappaB is important in regulating inflammatory responses, especially in macrophages. We presently investigated whether an NF-kappaB decoy, a synthetic oligodeoxynucleotide (ODN) imitating the NF-kappaB binding site, inhibited the inflammatory response after CCl(4) intoxication to prevent CCl(4)-induced hepatic injury and fibrosis. The NF-kappaB 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 CCl(4) were inhibited by the NF-kappaB decoy, which suppressed nuclear translocation of NF-kappaB in liver macrophages. Liver fibrosis induced by CCl(4) administration for 8 wk was suppressed by the NF-kappaB decoy, accompanied by diminished mRNA expression for transforming growth factor (TGF)-beta, procollagen type 1 alpha(1), and alpha-smooth muscle actin (SMA). In vitro, isolated liver macrophages showed increased DNA binding activity of NF-kappaB and inflammatory cytokine production after hydrogen peroxide treatment; both increases were inhibited significantly by the NF-kappaB decoy. In contrast, NF-kappaB decoy transferred to isolated hepatic stellate cells (HSC) had no effect on their morphological activation or alpha-SMA expression, although the decoy accelerated tumor necrosis factor (TNF)-alpha-induced apoptosis in activated HSC. The effect of NF-kappaB 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.
authors.affiliation: First Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Gakuhei
authors.initials: G
authors.lastname: Son
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iimuro
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Hirano
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
mesh_terms: D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis; D002251:Carbon Tetrachloride; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000378:metabolism* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D029082:Sendai virus / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D000893:Anti-Inflammatory Agents; D002251:Carbon Tetrachloride; D024042:Collagen Type I; D016207:Cytokines; D006861:Hydrogen Peroxide; D008081:Liposomes; D016328:NF-kappa B; D009841:Oligonucleotides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat