Peptide-directed suppression of a pro-inflammatory cytokine response.
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.
Liu
X Y
XY
Department of Microbiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
Robinson
D
D
Veach
R A
RA
Liu
D
D
Timmons
S
S
Collins
R D
RD
Hawiger
J
J
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D010455:Peptides; D010456:Peptides, Cyclic; C569011:cSN50 peptide