1. ¹Department of Internal Medicine II, Shimane University School of Medicine, Shimane, Japan
2. ²Department of Pathology and Laboratory of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
3. ³Division of Gastrointestinal Endoscopy, Shimane University Hospital, Shimane, Japan

Correspondence: Dr S Ishihara, MD, PhD, Department of Internal Medicine II, Shimane Medical University, 89-1, Enya-cho, Izumo, Shimane 693-8501, Japan. E-mail: si360405@med.shimane-u.ac.jp

Received 9 October 2007; Revised 28 February 2008; Accepted 28 February 2008; Published online 5 May 2008.

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-1, and TNF- in colon tissue. Therapeutic effects of AP-1 and NF-B 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-1, and TNF- in colonic tissue of mice with DSS-induced colitis. The AP-1 decoy therapeutic effect was comparable to that of NF-B 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.