Nuclear factor-kappa B activity and intestinal inflammation in dextran sulphate sodium (DSS)-induced colitis in mice is suppressed by gliotoxin

In acute DSS-induced colitis nuclear factor (NF)-kappa B-dependent inflamma tory cytokines including IL-1 and tumour necrosis factor-alpha (TNF-alpha) are up-regulated. Here we examined the effects of gliotoxin, a fungal metab olite known to inhibit NF-kappa B activity, on cytokine production by a mou se cell system in vitro and on intestinal inflammation and NF-kappa B activ ation in vivo. In vitro gliotoxin decreased TNF-alpha gene expression and p rotein production by RAW-264.7 mouse macrophage-like cells stimulated with lipopolysaccharide. In vivo, gliotoxin treatment of mice was begun on day 3 of 5% DSS application dissolved in the drinking water and continued until day 8. Gliotoxin treatment dose-dependently down-regulated colonic inflamma tion as assessed histologically and in parallel there was a suppression of colonic TNF-alpha and IL-1 alpha mRNA expression on day 8 as analysed by se miquantitative reverse transcriptase-polymerase chain reaction (P < 0.01). Furthermore, colonic NF-kappa B DNA-binding activity was increased in DSS-i nduced colitis and was suppressed by gliotoxin. These results demonstrate t he essential role of NF-kappa B in DSS-induced colitis and indicate a molec ular approach to the treatment of intestinal inflammatory disorders.