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  • Title: Inhibition of proinflammatory molecule production by adenovirus-mediated expression of a nuclear factor kappaB super-repressor in human intestinal epithelial cells.
    Author: Jobin C, Panja A, Hellerbrand C, Iimuro Y, Didonato J, Brenner DA, Sartor RB.
    Journal: J Immunol; 1998 Jan 01; 160(1):410-8. PubMed ID: 9551998.
    Abstract:
    NF-kappaB plays a major role in the transcriptional regulation of many proinflammatory genes in multiple cell lineages, including intestinal epithelial cells (IEC). Activation of NF-kappaB requires both phosphorylation and degradation of its natural cytoplasmic inhibitor, IkappaB. We tested whether a super-repressor of NF-kappaB activity, which is a mutated nondegradable IkappaB alpha resistant to phosphorylation and degradation, could be delivered into IEC using an adenoviral vector (Ad5 IkappaB) and determined the antiinflammatory potential of this inhibitor following different stimuli. We showed for the first time that recombinant adenovirus efficiently infected (>80%) transformed as well as primary IEC. Cytoplasmic levels of the NF-kappaB super-repressor protein were more than 50-fold higher than those of endogenous IkappaB, and this mutated IkappaB was resistant to IL-1beta-induced degradation. Immunofluorescent RelA nuclear staining was strongly inhibited in Ad5 IkappaB-infected IEC compared with control Ad5LacZ and NF-kappaB, but not AP-1 binding activity, was reduced by more than 70% as measured by electrophoretic mobility shift assay (EMSA). Induction of inducible nitric-oxide synthase (iNOS), IL-1beta, and IL-8 genes by IL-1beta, TNF-alpha, or PMA was blocked in Ad5 IkappaB-infected cells but not in Ad5 LacZ controls as assayed by RT-PCR and ELISA. In addition, IL-1beta-induced IL-8 secretion was totally inhibited by Ad5 IkappaB in primary colonic IEC. We conclude that an adenoviral vector efficiently transfers a nondegradable IkappaB in both transformed and native IEC. The strong inhibition of NF-kappaB activity and the resulting down-regulation of multiple proinflammatory molecules by Ad5 IkappaB suggests an exciting approach for in vivo intestinal gene therapy and illustrates the key role of NF-kappaB in transcriptional regulation of the inflammatory phenotype of IEC.
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