Decoy oligodeoxynucleotide targeting activator protein-1 (AP-1) attenuates intestinal inflammation in murine experimental colitis.
Various therapies are used for inflammatory bowel diseases (IBD), though none seem to be extremely effective. AP-1 is a major transcription factor that upregulates genes involved in immune and proinflammatory responses. We investigated decoy oligodeoxynucleotide (ODN) targeting AP-1 to prevent dextran sulfate sodium (DSS)-induced colitis in mice. Functional efficacies of synthetic decoy and scrambled ODNs were evaluated in vitro by a reporter gene luciferase assay and measuring flagellin-induced IL-8 expression by HCT-15 cells transfected with ODNs. Experimental colitis was induced in mice with a 2.5% DSS solution in drinking water for 7 days, and decoy or scrambled ODNs were intraperitoneally injected from days 2 to 5. Colitis was assessed by weight loss, colon length, histopathology, and detection of myeloperoxidase (MPO), IL-1beta, and TNF-alpha in colon tissue. Therapeutic effects of AP-1 and NF-kappaB decoy ODNs were compared. Transfection of AP-1 decoy ODN inhibited AP-1 transcriptional activity in reporter assays and flagellin-induced IL-8 production in vitro. In mice, AP-1 decoy ODN, but not scrambled ODN, significantly inhibited weight loss, colon shortening, and histological inflammation induced by DSS. Further, AP-1 decoy ODN decreased MPO, IL-1beta, and TNF-alpha in colonic tissue of mice with DSS-induced colitis. The AP-1 decoy therapeutic effect was comparable to that of NF-kappaB decoy ODN, which also significantly decreased intestinal inflammation. Double-strand decoy ODN targeting AP-1 effectively attenuated intestinal inflammation associated with experimental colitis in mice, indicating the potential of targeting proinflammatory transcription factors in new therapies for IBD.
Moriyama
Ichiro
I
Department of Internal Medicine II, Shimane University School of Medicine, Shimane, Japan.
Ishihara
Shunji
S
Rumi
M Azharul Karim
MA
Aziz
M D Monowar
MD
Mishima
Yoshiyuki
Y
Oshima
Naoki
N
Kadota
Chikara
C
Kadowaki
Yasunori
Y
Amano
Yuji
Y
Kinoshita
Yoshikazu
Y
D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009841:Oligonucleotides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D005456:Fluorescent Dyes; D016209:Interleukin-8; D009841:Oligonucleotides; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D016264:Dextran Sulfate; D008156:Luciferases; D016650:Fluorescein-5-isothiocyanate