Transcription factor decoy oligodeoxynucleotides to nuclear factor-kappaB inhibit reverse passive Arthus reaction in rat.
In the present study we investigated in the reverse passive Arthus reaction elicited in the rat skin the anti-inflammatory effect of double-stranded oligodeoxynucleotides (ODN) with consensus nuclear factor-kappaB (NF-kappaB) sequence as transcription factor decoys (TFD) to inhibit NF-kappaB binding to native DNA sites. Local administration of wild-type-, but not mutant-decoy ODN, dose-dependently reduced both plasma leakage and neutrophil infiltration in rat skin. Molecular analysis performed on soft tissue obtained from rat skin demonstrated: (1) an inhibition of NF-kappaB/DNA binding activity; (2) a decreased nuclear level of p50 and p65 NF-kappaB subunits; (3) an inhibition of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression, two inflammatory enzymes transcriptionally controlled by NF-kappaB. Furthermore, SN-50, a cell-permeable peptide capable of inhibiting the nuclear translocation of NF-kappaB complexes, as well as ammonium pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, exhibited a similar profile of activity of decoy ODN. Our results indicate that decoy ODN, acting as an in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent a novel strategy to modulate immune reactions.
D'Acquisto
F
F
Department of Experimental Pharmacology, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Naples, Italy.
Ianaro
A
A
Ialenti
A
A
Maffia
P
P
Maiuri
M C
MC
Carnuccio
R
R
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001183:Arthus Reaction / Q000378:metabolism*; D051546:Cyclooxygenase 2; D004247:DNA / Q000378:metabolism; D004347:Drug Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*; D014157:Transcription Factors / Q000494:pharmacology*
D000975:Antioxidants; D007527:Isoenzymes; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014157:Transcription Factors; C020972:pyrrolidine dithiocarbamic acid; D004247:DNA; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases