Decoy oligodeoxyribonucleotides and peptide nucleic acids-DNA chimeras targeting nuclear factor kappa-B: inhibition of IL-8 gene expression in cystic fibrosis cells infected with Pseudomonas aeruginosa.
Cystic fibrosis (CF) is characterized by a deep inflammatory process, with production and release of cytokines and chemokines, among which interleukin 8 (IL-8) represents one of the most important. Accordingly, there is a growing interest in developing therapies against IL-8, with the aim of reducing the excessive inflammatory response in the airways of CF patients. Since transcription factor NF-kappaB plays a critical role in IL-8 expression, the transcription factor decoy (TFD) strategy might be of interest. TFD is based on biomolecules mimicking the target sites of transcription factors (TFs) and able to interfere with TF activity when delivered to target cells. Here, we review the inhibitory effects of decoy oligodeoxyribonucleotides (ODNs) on expression of IL-8 gene and secretion of IL-8 by cystic fibrosis cells infected by Pseudomonas aeruginosa. In addition, the effects of decoy molecules based on peptide nucleic acids (PNAs) are discussed. In this respect PNA-DNA-PNA (PDP) chimeras are interesting: (a) unlike PNAs, they can be complexed with liposomes and microspheres; (b) unlike oligodeoxyribonucleotides (ODNs), they are resistant to DNAses, serum and cytoplasmic extracts; (c) unlike PNA/PNA and PNA/DNA hybrids, they are potent decoy molecules. Interestingly, PDP/PDP NF-kappaB decoy chimeras inhibit accumulation of pro-inflammatory mRNAs (including IL-8 mRNA) in P. aeruginosa infected IB3-1, cells reproducing the effects of decoy oligonucleotides. The effects of PDP/PDP chimeras, unlike ODN-based decoys, are observed even in absence of protection with lipofectamine. Since IL-8 is pivotal in pro-inflammatory processes affecting cystic fibrosis, inhibition of its functions might have a clinical relevance.
Gambari
Roberto
R
ER-GenTech and BioPharmaNet, Department of Biochemistry and Molecular Biology, University of Ferrara, Italy. gam@unife.it
Borgatti
Monica
M
Bezzerri
Valentino
V
Nicolis
Elena
E
Lampronti
Ilaria
I
Dechecchi
Maria Cristina
MC
Mancini
Irene
I
Tamanini
Anna
A
Cabrini
Giulio
G
D000818:Animals; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D020135:Peptide Nucleic Acids / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D011550:Pseudomonas aeruginosa
D016207:Cytokines; D016209:Interleukin-8; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D020135:Peptide Nucleic Acids; D004247:DNA