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Transcription Factor Oligodeoxynucleotides to NF-B Inhibit Transcription of IL-8 in Bronchial Cells

¹ Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, University-Hospital, Verona, Italy; ² ER-GenTech, Department of Biochemistry and Molecular Biology, ³ Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy

Correspondence and requests for reprints should be addressed to Roberto Gambari, PhD, Department of Biochemistry and Molecular Biology, Via L. Borsari 46, I-44100 Ferrara, Italy. E-mail: gam{at}unife.it or to Giulio Cabrini, MD, Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, University Hospital of Verona, Piazzale Stefani 1, I-37126 Verona, Italy. Email:giulio.cabrini{at}azosp.vr.it

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-, of the adhesion molecule intercellular adhesion molecule (ICAM)-1, and of the cytokines IL-1β and IL-6. Since consensus sequences for the TF, NF-B, are 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-B consensus sequences. IL-8 NF-B decoy ODN partially inhibited the P. aeruginosa–dependent transcription of IL-8, GRO-, and IL-6, whereas decoy ODNs to both HIV-1 long terminal repeat and Igk produced a strong, 80 to 85% inhibition of transcription of IL-8, without reducing that of GRO-, ICAM-1, IL-1β, and IL-6. In conclusion, intracellular delivery of "decoy" molecules aimed to compete with the TF, NF-B, is a promising strategy to obtain inhibition of IL-8 gene transcription.

Key Words: inflammation • lung • chemokines • cytokines • gene regulation

CLINICAL RELEVANCE Decoy oligonucleotides targeted to transcription factors are a promising tool to intervene in modulating critical genes involved in the immune response in the lungs of patients with cystic fibrosis.