Transcription factor decoy oligodeoxynucleotides to nuclear factor-kappa Binhibit reverse passive Arthus reaction in rat

In them present study we investigated in the reverse passive Arthus reactio n elicited in the rat skin the anti-inflammatory effect of double-stranded oligodeoxynucleotides (ODN) with consensus nuclear factor-KB (NF-kappaB) se quence as transcription factor decoys (TFD) to inhibit NF-KB binding to nat ive 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 inhibi tion of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression, two inflammatory enzymes transcriptionally controlled by NF-KB. Furthermore, SN-50, a cell-permeable peptide capable of inhibitin g the nuclear translocation. of NF-kappaB complexes, as well as ammonium py rrolidine 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 abilit y to bind to cognate recognition sequence, may represent a novel strategy t o modulate immune reactions.