Peptide-directed suppression of a pro-inflammatory cytokine response

Signal-dependent nuclear translocation of transcription factor nuclear fact or kappa B (NF-kappa B) is required for the activation of downstream target genes encoding the mediators of immune and inflammatory responses. To inhi bit this inducible signaling to the nucleus, we designed a cyclic peptide ( cSN50) containing a cell-permeable motif and a cyclized form of the nuclear localization sequence for the p50-NF-kappa B1 subunit of NF-kappa B. When delivered into cultured macrophages treated with the pro-inflammatory agoni st lipopolysaccharide, cSN50 was a more efficient inhibitor of NF-kappa B n uclear import than its linear analog. When delivered into mice challenged w ith lipopolysaccharide, cSN50 potently blocked the production of proinflamm atory cytokines (tumor necrosis factor alpha and interferon gamma) and sign ificantly reduced the lethality associated with ensuing endotoxic shock. Ba sed on specificity studies conducted with a mutated form of cSN50, a functi onal nuclear localization motif is required for this protective effect. Tak en together, our findings demonstrate effective targeting of a cell-permeab le peptide that attenuates cytokine signaling in vivo. This new class of bi ological response modifiers may be applicable to the control of systemic in flammatory reactions.