Therapeutic effect of intracolonically administered nuclear factor κB (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis

Abstract

SUMMARY Cytokines such as IL-1, tumour necrosis factor-alpha (TNF-α), IL-6 and IL-8 are increased in inflamed colonic mucosa after administration of mouse DSS. Nuclear factor κB (NF-κB) is a transcription factor which regulates the expression of these cytokine genes. The effect of intracolonically administered NF-κB (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-α 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-κB p65 in the antisense oligonucleotide-treated group, although it was increased in the colitis group. These results suggest that intracolonic administration of NF-κB antisense oligonucleotide may be effective in ulcerative colitis.