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首页> 外文期刊>American Journal of Physiology >Selective inactivation of NF-kappaB in the liver using NF-kappaB decoy suppresses CCl4-induced liver injury and fibrosis.
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Selective inactivation of NF-kappaB in the liver using NF-kappaB decoy suppresses CCl4-induced liver injury and fibrosis.

机译：使用NF-kappaB诱饵对肝脏中的NF-kappaB进行选择性失活可以抑制CCl4诱导的肝损伤和纤维化。

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摘要

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.
机译：各种原因引起的持续性肝炎可导致肝纤维化。转录因子NF-κB在调节炎症反应，特别是在巨噬细胞中很重要。我们目前调查是否NF-kappaB诱饵，模拟NF-kappaB结合位点的合成寡聚脱氧核苷酸（ODN），抑制CCl（4）中毒后的炎症反应，以防止CCl（4）诱导的肝损伤和纤维化。使用日本血凝病毒（HVJ）-脂质体方法，通过注射小鼠脾脏将NF-κB诱饵引入肝脏。 ODN主要转移至正常或纤维化肝脏中的巨噬细胞。一次用CCl（4）攻击后，血清转氨酶的增加和炎性细胞因子的产生被NF-κB诱饵抑制，后者抑制了肝巨噬细胞中NF-κB的核转运。 NF-kappaB诱饵抑制了CCl（4）给药8周引起的肝纤维化，并伴有转化生长因子（TGF）-β，胶原蛋白1型alpha（1）和α-平滑肌肌动蛋白的mRNA表达降低。 （SMA）。在体外，分离的肝巨噬细胞在过氧化氢处理后显示出增加的NF-κBDNA结合活性和炎性细胞因子的产生。 NF-κB诱饵均显着抑制了两种增加。相比之下，尽管诱饵在激活的HSC中加速了肿瘤坏死因子（TNF）-α诱导的凋亡，但转移至分离的肝星状细胞（HSC）的NF-κB诱饵对其形态激活或α-SMA表达没有影响。 NF-κB诱饵抑制纤维化的作用可能主要来自对肝巨噬细胞的抗炎作用，而其对活化的HSC的直接促凋亡作用可能贡献很小。

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