Background: Nuclear factor-kappa B (NF-kappa B) is a key transcriptional regulator of inflammatory bowel disease (IBD). Aim: To investigate the therapeutic potential of a locally administered "non-viral'' nuclear factor-kappa B decoy (NF kappa BD) in multiple experimental models of IBD. Methods: A fully phosphorothioated decoy oligonucleotide with improved stability that specifically binds NF kappa B and blocks inflammatory mediators regulated by this transcription factor without the help of viral envelope-assisted delivery was developed. The therapeutic effects of NF kappa BD were studied in the trinitrobenzene sulphonic acid, oxazolone and dextran sodium sulphate induced colitis models. Results: Intracolonic administration of NFkBD results in the delivery of NF kappa BD to inflammatory cells and a reduction of NF-kappa B heterodimers. In the T helper cell 1-driven trinitrobenzene sulphonic acid-induced colitis model, mice receiving NFk kappa BD 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 proinflammatory markers, including tumour necrosis factor alpha, interleukin delta, interleukin 1 beta and monocyte chemotactic protein 1. NF kappa BD 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 NF kappa BD-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'' NF kappa BD as a cross-functional therapeutic in IBD, and show for the first time that it can facilitate the restoration of colon homeostasis and function.
机构:
UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
AUPHAN, N
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DIDONATO, JA
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
DIDONATO, JA
;
ROSETTE, C
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
ROSETTE, C
;
HELMBERG, A
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
HELMBERG, A
;
KARIN, M
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
AUPHAN, N
;
DIDONATO, JA
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
DIDONATO, JA
;
ROSETTE, C
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
ROSETTE, C
;
HELMBERG, A
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UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA
HELMBERG, A
;
KARIN, M
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机构:
UNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USAUNIV CALIF SAN DIEGO, SCH MED,CTR GENET MOLEC,DEPT PHARMACOL, PROGRAM BIOMED SCI, LA JOLLA, CA 92093 USA