Lipopolysaccharide Mediates Endothelial Apoptosis by a FADD-dependent Pathway*
- From the ‡Department of Pathology and Laboratory Medicine, University of British Columbia and St. Paul’s Hospital, Vancouver, British Columbia, Canada V6Z 1Y6 and the Departments of¶Molecular Biotechnology and §Medicine, University of Washington, Seattle, Washington 98195
Abstract
Endothelial cells play a pivotal role in the inflammatory process by coordinating the recruitment of inflammatory cells to sites of tissue injury. Lipopolysaccharide (LPS) activates many of the proinflammatory and procoagulant responses of endothelial cells, and endothelial injury is thought to play a crucial role in the pathogenesis of septic shock due to Gram-negative bacteria. The receptor used by LPS to signal endothelial responses has not been identified. It is also not known how LPS induces endothelial injury/death. In this study, we demonstrate that LPS mediates endothelial apoptosis by a FADD-dependent pathway. FADD is a death domain-containing protein that binds to certain members of the tumor necrosis factor receptor family, namely TNFR1, Fas, and DR3. However, none of these receptors appear to be involved in LPS-mediated death, suggesting that LPS may utilize a novel death domain-containing protein to transduce a death signal.
Footnotes
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↵* This work was supported by Grants CLN-1002-42547 and MT-14373 from the Medical Research Council of Canada with funds from the British Columbia Lung Association.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.
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↵‖ Clinician-Scientist of the Medical Research Council of Canada. To whom correspondence should be addressed: McDonald Research Laboratories, St. Paul’s Hospital, 1081 Burrard St., Vancouver, British Columbia, Canada V6Z 1Y6. Tel.: 604-631-5346; Fax: 604-631-5351; E-mail: akarsan{at}prl.pulmonary.ubc.ca.
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↵2 A. Karsan, unpublished data.
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↵3 P. Chaudhary and L. Hood, unpublished data.
- Abbreviations:
- LPS
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lipopolysaccharide
- TNF
-
tumor necrosis factor
- TNFR1
-
TNF receptor 1
- DD
-
death domain
- MTT
-
(3-[4′,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide)
- BHK
-
baby hamster kidney
- PARP
-
poly(ADP-ribose) polymerase
- CHX
-
cycloheximide
- DN
-
dominant negative.
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- Received December 1, 1997.
- Revision received May 2, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
