Peptide-directed Suppression of a Pro-inflammatory Cytokine Response

• Published in: The Journal of biological chemistry Vol. 275; no. 22; pp. 16774 - 16778
• Main Authors: Yan Liu, Xue, Robinson, Daniel, Veach, Ruth Ann, Liu, Danya, Timmons, Sheila, Collins, Robert D., Hawiger, Jacek
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-06-2000; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Cells, Cultured; Cytokines - antagonists & inhibitors; Cytokines - physiology; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - physiology; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Membrane Proteins - blood; Membrane Proteins - chemistry; Membrane Proteins - pharmacology; Mice; Molecular Sequence Data; NF-^KB protein; NF-kappa B - antagonists & inhibitors; Peptides - blood; Peptides - chemistry; Peptides - pharmacology; Peptides, Cyclic - blood; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Spleen - cytology; Spleen - drug effects; Spleen - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C000083200

Signal-dependent nuclear translocation of transcription factor nuclear factor κB (NF-κB) is required for the activation of downstream target genes encoding the mediators of immune and inflammatory responses. To inhibit 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-κB1 subunit of NF-κB. When delivered into cultured macrophages treated with the pro-inflammatory agonist lipopolysaccharide, cSN50 was a more efficient inhibitor of NF-κB nuclear import than its linear analog. When delivered into mice challenged with lipopolysaccharide, cSN50 potently blocked the production of proinflammatory cytokines (tumor necrosis factor α and interferon γ) and significantly reduced the lethality associated with ensuing endotoxic shock. Based on specificity studies conducted with a mutated form of cSN50, a functional nuclear localization motif is required for this protective effect. Taken together, our findings demonstrate effective targeting of a cell-permeable peptide that attenuates cytokine signaling in vivo. This new class of biological response modifiers may be applicable to the control of systemic inflammatory reactions.