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Originally published In Press as doi:10.1074/jbc.C000083200 on April 5, 2000

J. Biol. Chem., Vol. 275, Issue 22, 16774-16778, June 2, 2000
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Peptide-directed Suppression of a Pro-inflammatory Cytokine Response*

Xue Yan LiuDagger , Daniel RobinsonDagger , Ruth Ann VeachDagger , Danya LiuDagger , Sheila TimmonsDagger , Robert D. Collins§, and Jacek HawigerDagger

From the Departments of Dagger  Microbiology and Immunology and § Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363

Signal-dependent nuclear translocation of transcription factor nuclear factor kappa B (NF-kappa B) 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-kappa B1 subunit of NF-kappa B. When delivered into cultured macrophages treated with the pro-inflammatory agonist lipopolysaccharide, cSN50 was a more efficient inhibitor of NF-kappa B 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.

* This work was supported in part by USPHS National Institutes of Health Grant R01 DK54072. The use of core facilities in this study was supported by USPHS, National Institutes of Health Grant 2P30 CA 68485-05 to the Vanderbilt-Ingram Cancer Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Vanderbilt University Medical Center, MCN 5326, Nashville, TN 37232. Tel.: 615-343-8280; Fax: 615-343-8278; E-mail: jacek.hawiger@mcmail.vanderbilt. edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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