Ruth Veach
Last active: 4/25/2016

Peptide-directed suppression of a pro-inflammatory cytokine response.

Liu XY, Robinson D, Veach RA, Liu D, Timmons S, Collins RD, Hawiger J
J Biol Chem. 2000 275 (22): 16774-8

PMID: 10751381 · DOI:10.1074/jbc.C000083200

Signal-dependent nuclear translocation of transcription factor nuclear factor kappaB (NF-kappaB) 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-kappaB1 subunit of NF-kappaB. When delivered into cultured macrophages treated with the pro-inflammatory agonist lipopolysaccharide, cSN50 was a more efficient inhibitor of NF-kappaB nuclear import than its linear analog. When delivered into mice challenged with lipopolysaccharide, cSN50 potently blocked the production of proinflammatory cytokines (tumor necrosis factor alpha and interferon gamma) 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.

MeSH Terms (14)

Amino Acid Sequence Animals Cells, Cultured Cytokines Inflammation Mediators Lipopolysaccharides Macrophages Membrane Proteins Mice Molecular Sequence Data NF-kappa B Peptides Peptides, Cyclic Spleen

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