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)-kappaB-dependent inflammatory cytokines including IL-1 and tumour necrosis factor-alpha (TNF-alpha) are up-regulated. Here we examined the effects of gliotoxin, a fungal metabolite known to inhibit NF-kappaB activity, on cytokine production by a mouse cell system in vitro and on intestinal inflammation and NF-kappaB activation in vivo. In vitro gliotoxin decreased TNF-alpha gene expression and protein 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 inflammation as assessed histologically and in parallel there was a suppression of colonic TNF-alpha and IL-1alpha mRNA expression on day 8 as analysed by semiquantitative reverse transcriptase-polymerase chain reaction (P < 0.01). Furthermore, colonic NF-kappaB DNA-binding activity was increased in DSS-induced colitis and was suppressed by gliotoxin. These results demonstrate the essential role of NF-kappaB in DSS-induced colitis and indicate a molecular approach to the treatment of intestinal inflammatory disorders.
Herfarth
H
H
Department of Internal Medicine I, Regensburg, and Department of Clinical Chemistry and Pathobiochemistry, Klinikum re. d. Isar, Munich, Germany. hherf@t-online.de
Brand
K
K
Rath
H C
HC
Rogler
G
G
Schölmerich
J
J
Falk
W
W
D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005912:Gliotoxin / Q000008:administration & dosage / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D005912:Gliotoxin; D016264:Dextran Sulfate