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Transcription Factor Oligodeoxynucleotides to NF-{kappa}B Inhibit Transcription of IL-8 in Bronchial Cells.

By Bezzerri V, Borgatti M, Nicolis E, Lampronti I, Dechecchi MC, Mancini I, Rizzotti P, Gambari R and Cabrini G.


Chronic pulmonary inflammation in patients affected by cystic fibrosis (CF) is characterized by massive bronchial infiltrates of neutrophils, which is sustained by the interaction of pathogens (e.g. Pseudomonas aeruginosa) with surface bronchial cells. To explore new treatment options focused on the reduction of neutrophil chemotaxis, we applied the transcription factor (TF) decoy approach, based on the intracellular delivery of double stranded oligodeoxynucleotides (ODNs) causing inhibition of the binding of TF-related proteins to the different consensus sequences in the promoter of specific genes. In CF bronchial IB3-1 cells, P.aeruginosa induced transcription of the neutrophil chemokines IL-8 and GRO-gamma of the adhesion molecule ICAM-1, and of the cytokines IL-1beta and IL-6. Since consensus sequences for the TF, NF-kappaB, is contained in the promoters of all these genes, IB3-1, CuFi-1, Beas-2B and CaLu-3 cells were transfected with double stranded TF "decoy" ODNs mimicking different NF-kappaB consensus sequences. IL-8 NF-kappaB decoy ODN partially inhibited the P.aeruginosa-dependent transcription of IL-8, GRO-gamma and IL-6, whereas decoy ODNs to both HIV-1 LTR and Igk produced a strong, 80 to 85% inhibition of transcription of IL-8, without reducing that of GRO-gamma, ICAM-1, IL-1beta and IL-6. In conclusion, intracellular delivery of "decoy" molecules aimed to compete with the TF, NF-kappaB, is a promising strategy to obtain inhibition of of IL-8 gene transcription

Year: 2008
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