Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice.
Chronic intestinal inflammation induced by 2,4,6,-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn's disease. Here, we show that the transcription factor NF-kappa B p65 was strongly activated in TNBS-induced colitis and in colitis of interleukin-10-deficient mice. Local administration of p65 antisense phosphorothioate oligonucleotides abrogated clinical and histological signs of colitis and was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. The data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and suggest a potential therapeutic utility of p65 antisense oligonucleotides as a novel molecular approach for the treatment of patients with Crohn's disease.
Neurath
M F
MF
Laboratory of Immunology, University of Mainz, Germany.
Pettersson
S
S
Meyer zum Büschenfelde
K H
KH
Strober
W
W
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D051996:Transcription Factor RelA; D014302:Trinitrobenzenesulfonic Acid
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D051996:Transcription Factor RelA; D016753:Interleukin-10; D014302:Trinitrobenzenesulfonic Acid; D004247:DNA