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J. Biol. Chem., Vol. 277, Issue 43, 40567-40574, October 25, 2002
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From the Departments of Shiga-like toxin (SLT) has been implicated in the
pathogenesis of hemolytic uremic syndrome and its attendant endothelial cell (EC) injury. Key serotypes of Escherichia coli produce
SLT-1 in addition to another highly pro-inflammatory molecule,
lipopolysaccharide (LPS). It has previously been established that SLT-1
induces EC apoptosis and that LPS enhances this effect. LPS alone has
no affect on human EC viability, and the mechanism for this enhancement remains unknown. In the present report, we demonstrate that SLT-1 sensitizes EC to LPS-induced apoptosis. Pretreatment with SLT-1 sensitized EC to LPS-induced apoptosis, whereas pretreatment with LPS
did not influence SLT-1-induced apoptosis. SLT-1 exposure resulted in
decreased expression of FLICE-like inhibitory protein (FLIP), an
anti-apoptotic protein that has previously been shown to block
LPS-induced apoptosis. This SLT-1-mediated decrease in FLIP expression
preceded the onset of apoptosis elicited by SLT-1 alone or in
combination with LPS. SLT-1-mediated decrements in FLIP expression
correlated in a dose- and time-dependent manner with
sensitization to LPS-induced apoptosis. Finally, transient or stable
overexpression of FLIP protected against LPS enhancement of
SLT-1-induced apoptosis, and this protection corresponded with sustained expression of FLIP. Together, these data suggest that SLT-1
sensitizes EC to LPS-induced apoptosis by inhibiting FLIP expression.
Shiga-like Toxin Inhibition of FLICE-like Inhibitory Protein
Expression Sensitizes Endothelial Cells to Bacterial
Lipopolysaccharide-induced Apoptosis*
,, and
Medicine and
§ Surgery, University of Washington School of Medicine,
Seattle, Washington 98104 and ¶ Immunology and Disease Resistance
Laboratory, United States Department of Agriculture-Agricultural
Research Service, Beltsville, Maryland 20705
*
This work was supported by National Institutes of Health
Grants GM07037, GM42686, HL18645, and HL03174.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: Immunology and
Disease Resistance Laboratory, USDA Agricultural Research Service/ANRI, BARC-East, Bldg. 1040, Rm. 2, Beltsville, MD 20705-2350. Tel.: 301-504-5066; Fax: 301-504-9498; E-mail:
dbanner@anri.barc.usda.gov.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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