Therapeutic effect of intracolonically administered nuclear factor κB (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis
Therapeutic effect of intracolonically administered nuclear factor κB (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis
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DOI：
10.1046/j.1365-2249.2000.01183.x
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发表时间：
2000-04-01
影响因子：
4.6
通讯作者：
Katsu, K
中科院分区：
文献类型：
--
作者：
Murano, M;Maemura, K;Katsu, K
给药小鼠DSS后，炎症结肠黏膜中IL-1、肿瘤坏死因子- α (tnf - α)、IL-6和IL-8等细胞因子升高。核因子κ B （nf - κ B）是调节这些细胞因子基因表达的转录因子。采用含5% DSS的饮用水，观察结肠内给药NF-kappa B （p65）反义硫代寡核苷酸对小鼠DSS诱导结肠炎的影响。第0天给予反义寡核苷酸后，代表临床症状的疾病活动指数（DAI）改善，组织学评分降低；直肠黏膜IL-1、IL-6、tnf - α浓度均低于对照组。当第2天开始使用反义寡核苷酸而不是第7天开始使用时，也观察到临床和组织学改善。此外，用激光共聚焦显微镜研究了反义寡核苷酸的分布。在结肠粘膜中，寡核苷酸主要定位于固有层细胞，但也定位于上皮细胞。均质直肠黏膜Western blot分析显示，反义寡核苷酸处理组NF-kappa B p65表达降低，结肠炎组NF-kappa B p65表达升高。这些结果提示，在结肠内给予nf - κ B反义寡核苷酸可能对溃疡性结肠炎有效。
Cytokines such as IL-1, tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 are increased in inflamed colonic mucosa after administration of mouse DSS. Nuclear factor kappa B (NF-kappa B) is a transcription factor which regulates the expression of these cytokine genes. The effect of intracolonically administered NF-kappa B (p65) antisense phosphorothioate oligonucleotide was examined in mouse DSS-induced colitis using drinking water containing 5% DSS. When antisense oligonucleotide was given on day 0, the disease activity index (DAI) representing clinical symptoms improved and the histological score decreased; furthermore, IL-1, IL-6, and TNF-alpha concentrations in rectal mucosa were lower compared with the control group. Clinical and histological improvement was also observed when antisense oligonucleotide was begun on day 2 but not on day 7. In addition, the distribution of antisense oligonucleotides was investigated by confocal laser microscopy. In colonic mucosa, oligonucleotides were predominantly localized to cells in the lamina propria, but also in the epithelium. Western blot analysis using homogenized rectal mucosa showed the decreased expression of NF-kappa B p65 in the antisense oligonucleotide-treated group, although it was increased in the colitis group. These results suggest that intracolonic administration of NF-kappa B antisense oligonucleotide may be effective in ulcerative colitis.