Decoy oligodeoxynucleotide targeting activator protein-1 (AP-1) attenuates intestinal inflammation in murine experimental colitis.

Abstract

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.

• Authors: Ichiro Moriyama, Shunji Ishihara, M Azharul Karim Rumi, M D Monowar Aziz, Yoshiyuki Mishima, Naoki Oshima, Chikara Kadota, Yasunori Kadowaki, Yuji Amano, Yoshikazu Kinoshita
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 88 Issue 6 Pg. 652-63 (Jun 2008) ISSN: 1530-0307 [Electronic] United States
• PMID: 18458670 (Publication Type: Journal Article)

Chemical References

• Fluorescent Dyes
• Interleukin-8
• Oligonucleotides
• RNA, Messenger
• Transcription Factor AP-1
• Dextran Sulfate
• Luciferases
• Fluorescein-5-isothiocyanate

Topics

• Animals
• Cell Culture Techniques
• Cell Line, Tumor
• Colitis, Ulcerative (chemically induced, metabolism, pathology)
• Colonic Neoplasms (pathology)
• Dextran Sulfate (pharmacology)
• Flow Cytometry
• Fluorescein-5-isothiocyanate (metabolism)
• Fluorescent Dyes (metabolism)
• Genes, Reporter
• Humans
• Inflammation (drug therapy)
• Interleukin-8 (antagonists & inhibitors)
• Luciferases (metabolism)
• Mice
• Mice, Inbred BALB C
• Oligonucleotides (pharmacology)
• RNA, Messenger (metabolism)
• Specific Pathogen-Free Organisms
• Transcription Factor AP-1 (metabolism)
• Transcription, Genetic (drug effects)
• Transfection