Use of phosphorothioate-modified oligodeoxynucleotides to inhibit NF-kappaB expression and lymphocyte function.

NF-kappaB is a potential target for immunosuppressive therapy. Two methods were evaluated to inhibit NF-kappaB: the antisense (AS) approach in which single-stranded oligodeoxynucleotides (ODNs) bind the mRNA for the RelA subunit of NF-kappaB and the transcription factor decoy (TFD) approach in which double-stranded ODNs bind the NF-kappaB protein. AS and TFD inhibited NF-kappaB binding and decreased total IgG and anti-dsDNA antibody production in splenocytes from the BXSB/Yaa autoimmune mouse strain. TNF-alpha expression was reduced by AS and TFD, as were the levels of IL-2. But AS effects did not last beyond 24 h, whereas TFD inhibited cytokine production after 72 h. AS had no effect upon IL-6, while the TFD reduced the secretion of IL-6. Therefore, the suppression of immune response mediators by AS or TFD, through inhibition of NF-kappaB, is substantial. These inhibitors can serve as novel choices for therapy in the treatment of autoimmune disorders. Copyright 1998 Academic Press.