Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-κB decoy oligonucleotides
Stefan Fichtner-Feigl, … , Warren Strober, Atsushi Kitani
Stefan Fichtner-Feigl, … , Warren Strober, Atsushi Kitani
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3057-3071. https://doi.org/10.1172/JCI24792.
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Research Article Immunology

Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-κB decoy oligonucleotides

Abstract

The Th1 and Th2 T cell responses that underlie inflammatory bowel diseases (IBDs) are likely to depend on NF-κB transcriptional activity. We explored this possibility in studies in which we determined the capacity of NF-κB decoy oligodeoxynucleotides (decoy ODNs) to treat various murine models of IBD. In initial studies, we showed that i.r. (intrarectal) or i.p. administration of decoy ODNs encapsulated in a viral envelope prevented and treated a model of acute trinitrobenzene sulfonic acid–induced (TNBS-induced) colitis, as assessed by clinical course and effect on Th1 cytokine production. In further studies, we showed that NF-κB decoy ODNs were also an effective treatment of a model of chronic TNBS-colitis, inhibiting both the production of IL-23/IL-17 and the development of fibrosis that characterizes this model. Treatment of TNBS-induced inflammation by i.r. administration of NF-κB decoy ODNs did not inhibit NF-κB in extraintestinal organs and resulted in CD4+ T cell apoptosis, suggesting that such treatment is highly focused and durable. Finally, we showed that NF-κB decoy ODNs also prevented and treated oxazolone-colitis and thus affect a Th2-mediated inflammatory process. In each case, decoy administration led to inflammation-clearing effects, suggesting a therapeutic potency applicable to human IBD.

Authors

Stefan Fichtner-Feigl, Ivan J. Fuss, Jan C. Preiss, Warren Strober, Atsushi Kitani

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Treatment of chronic TNBS-colitis by NF-κB decoy ODNs — effect on cytoki...
Treatment of chronic TNBS-colitis by NF-κB decoy ODNs — effect on cytokine production and NF-κB binding activity. (A and B) Chronic TNBS-colitis was induced by 7 weekly i.r. administrations of TNBS in ethanol. Mice were treated with NF-κB decoy ODNs (or scrambled ODNs) via an i.r. route (day 37 and day 44) or via an i.p. route (days 37–39 and days 44–46). (A) Cytokine production of colonic lamina propria cells on day 49 after the initial TNBS administration. Cells were extracted from the lamina propria and cultured for 48 hours in the presence of stimulants (see Methods). Cytokine concentrations were determined in culture supernatants by ELISA. Data shown are mean values ± SD and are representative of 2 independent experiments. (B) DNA-binding activity of p65 on day 49 after initial TNBS administration in nuclear extracts from colonic lamina propria cells, measured by TransFactor assay. *P < 0.01.