Selective inactivation of NF-kappaB in the liver using NF-kappaB decoy suppresses CCl4-induced liver injury and fibrosis
| Autor: | Gakuhei Son, Jiro Fujimoto, Yuji Iimuro, Yasufumi Kaneda, Ekihiro Seki, Tadamichi Hirano |
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| Rok vydání: | 2007 |
| Předmět: |
Liver Cirrhosis
Male Time Factors Physiology Anti-Inflammatory Agents Oligonucleotides Apoptosis Sendai virus Rats Sprague-Dawley chemistry.chemical_compound Mice Fibrosis Transforming Growth Factor beta Macrophage Carbon Tetrachloride Cells Cultured Liver injury Gastroenterology Gene Transfer Techniques NF-kappa B Liver Cytokines Chemical and Drug Induced Liver Injury Kupffer Cells Active Transport Cell Nucleus CCL4 Biology Transfection Collagen Type I Physiology (medical) medicine Animals RNA Messenger Transcription factor Cell Nucleus Hepatology NF-κB Genetic Therapy Hydrogen Peroxide medicine.disease Actins Rats Mice Inbred C57BL Disease Models Animal chemistry Immunology Liposomes Cancer research Hepatic fibrosis |
| Zdroj: | American journal of physiology. Gastrointestinal and liver physiology. 293(3) |
| ISSN: | 0193-1857 |
| Popis: | Sustained hepatic inflammation induced by various causes can lead to liver fibrosis. Transcription factor NF-κB is important in regulating inflammatory responses, especially in macrophages. We presently investigated whether an NF-κB decoy, a synthetic oligodeoxynucleotide (ODN) imitating the NF-κB binding site, inhibited the inflammatory response after CCl4 intoxication to prevent CCl4-induced hepatic injury and fibrosis. The NF-κB 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-κB decoy, which suppressed nuclear translocation of NF-κB in liver macrophages. Liver fibrosis induced by CCl4 administration for 8 wk was suppressed by the NF-κB decoy, accompanied by diminished mRNA expression for transforming growth factor (TGF)-β, procollagen type 1 α1, and α-smooth muscle actin (SMA). In vitro, isolated liver macrophages showed increased DNA binding activity of NF-κB and inflammatory cytokine production after hydrogen peroxide treatment; both increases were inhibited significantly by the NF-κB decoy. In contrast, NF-κB decoy transferred to isolated hepatic stellate cells (HSC) had no effect on their morphological activation or α-SMA expression, although the decoy accelerated tumor necrosis factor (TNF)-α-induced apoptosis in activated HSC. The effect of NF-κB 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. |
| Databáze: | OpenAIRE |
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