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J. Biol. Chem., Vol. 279, Issue 18, 19239-19246, April 30, 2004

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Suppression of Staphylococcal Enterotoxin B-induced Toxicity by a Nuclear Import Inhibitor^*

Danya Liu, Xue Yan Liu, Daniel Robinson, Christie Burnett, Charity Jackson, Louis Seele, Ruth Ann Veach, Sheila Downs, Robert D. Collins¶, Dean W. Ballard, and Jacek Hawiger||

From the Departments of Microbiology and Immunology and ^¶Pathology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Staphylococcal enterotoxin B and related toxins that target T cells have the capacity to elicit systemic inflammation, tissue injury, and death. Genes that encode mediators of inflammation can be globally inhibited by blocking the nuclear import of stress-responsive transcription factors. Here we show that cell-permeant peptides targeting Rch1/importin /karyopherin 2, a nuclear import adaptor protein, are delivered to T cells where they inhibit the staphylococcal enterotoxin B-induced production of inflammatory cytokines ex vivo in cultured primary spleen cells and in vivo. The systemic production of tumor necrosis factor , interferon , and interleukin-6 was attenuated in mice either by a cell-permeant cyclized form of SN50 peptide or by a transgene whose product suppresses the nuclear import of transcription factor nuclear factor B in T cells. The extent of liver apoptosis and hemorrhagic necrosis was also reduced, which correlated with significantly decreased mortality rates. These findings highlight nuclear import inhibitors as a potentially useful countermeasure for staphylococcal enterotoxin B and other toxins that trigger harmful systemic inflammatory responses.

Received for publication, December 9, 2003 , and in revised form, January 12, 2004.

^* This work was supported in part by USPHS National Institutes of Health Grants HL69542, HL62356, HL68744, DK54072, and CA82556. 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. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: 4400 Belmont Park Terr., No. 115, Nashville, TN 37215.

^|| To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Ave. S., A-5321 MCN, Nashville, TN 37232-2363. Tel.: 615-343-8280; Fax: 615-343-8278; E-mail: jacek.hawiger{at}vanderbilt.edu.

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