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Non-viral delivery of nuclear factor-kappaB decoy ameliorates murine inflammatory bowel disease and restores tissue homeostasis
- Source :
- Gut. 56(4)
- Publication Year :
- 2006
-
Abstract
- Background: Nuclear factor-κB (NF-κB) is a key transcriptional regulator of inflammatory bowel disease (IBD). Aim: To investigate the therapeutic potential of a locally administered “non-viral” nuclear factor-κB decoy (NFκBD) in multiple experimental models of IBD. Methods: A fully phosphorothioated decoy oligonucleotide with improved stability that specifically binds NF-κB and blocks inflammatory mediators regulated by this transcription factor without the help of viral envelope-assisted delivery was developed. The therapeutic effects of NFκBD were studied in the trinitrobenzene sulphonic acid, oxazolone and dextran sodium sulphate induced colitis models. Results: Intracolonic administration of NFκBD results in the delivery of NFκBD to inflammatory cells and a reduction of NF-κB heterodimers. In the T helper cell 1-driven trinitrobenzene sulphonic acid-induced colitis model, mice receiving NFκBD treatment exhibit a dose-dependent reduction in disease severity and a more rapid recovery to normal body weight, similar to a clinically relevant dose of budesonide. Clinical efficacy was corroborated by considerable reductions in colitis pathology and tissue levels of several pro-inflammatory markers, including tumour necrosis factor α, interleukin 6, interleukin 1β and monocyte chemotactic protein 1. NFκBD also mitigates disease activity in the T helper cell 2-like oxazolone colitis and epithelial injury-related acute dextran sodium sulphate colitis models. Interestingly, restoration of tissue homeostasis is observed in NFκBD-treated animals with the rapid re-emergence of functional goblet cells and a return to normal patterns of cell proliferation in the mucosal epithelium and smooth muscle cell layers. Conclusions: These data support the potential use of “naked” NFκBD as a cross-functional therapeutic in IBD, and show for the first time that it can facilitate the restoration of colon homeostasis and function.
- Subjects :
- Budesonide
Male
Colon
Inflammatory bowel disease
Oxazolone
chemistry.chemical_compound
Mice
Medicine
Animals
Homeostasis
Colitis
Interleukin 6
Tissue homeostasis
Mice, Inbred BALB C
Microscopy, Confocal
biology
business.industry
Dextran Sulfate
Inflammatory Bowel Disease
Gastroenterology
Gene Transfer Techniques
NF-kappa B
T helper cell
Genetic Therapy
medicine.disease
Inflammatory Bowel Diseases
Ulcerative colitis
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
chemistry
Oligodeoxyribonucleotides
Trinitrobenzenesulfonic Acid
Immunology
Cancer research
biology.protein
Female
Inflammation Mediators
business
medicine.drug
Subjects
Details
- ISSN :
- 00175749
- Volume :
- 56
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....5fb182264fdf1739cd0d35f0f3f82667