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

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 r egulates the expression of these cytokine genes. The effect of intracolonic ally administered NF-kappa B (p65) antisense phosphorothioate oligonucleoti de was examined in mouse DSS-induced colitis using drinking water containin g 5% DSS. When antisense oligonucleotide was given on day 0, the disease ac tivity index (DAI) representing clinical symptoms improved and the histolog ical 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 w as begun on day 2 but not on day 7. In addition, the distribution of antise nse oligonucleotides was investigated by confocal laser microscopy. In colo nic mucosa, oligonucleotides were predominantly localized to cells in the l amina propria, but also in the epithelium. Western blot analysis using homo genized rectal mucosa showed the decreased expression of NF-kappa B p65 in the antisense oligonucleotide-treated group, although it was increased in t he colitis group. These results suggest that intracolonic administration of NF-kappa B antisense oligonucleotide may be effective in ulcerative coliti s.