Suppression of Staphylococcal Enterotoxin B-induced Toxicity by a Nuclear Import Inhibitor.
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 alpha/karyopherin alpha 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 alpha, interferon gamma, 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 kappa 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.
Liu
Danya
D
Departments of Microbiology and Immunology and Pathology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Liu
Xue Yan
XY
Robinson
Daniel
D
Burnett
Christie
C
Jackson
Charity
C
Seele
Louis
L
Veach
Ruth Ann
RA
Downs
Sheila
S
Collins
Robert D
RD
Ballard
Dean W
DW
Hawiger
Jacek
J
D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability; D016207:Cytokines / Q000037:antagonists & inhibitors; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism; D028901:alpha Karyopherins / Q000037:antagonists & inhibitors
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D004768:Enterotoxins; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D028901:alpha Karyopherins; C087978:karyopherin alpha 2; C031818:enterotoxin B, staphylococcal