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Originally published In Press as doi:10.1074/jbc.M407190200 on September 1, 2004
J. Biol. Chem., Vol. 279, Issue 46, 48434-48442, November 12, 2004
Nuclear Import of Proinflammatory Transcription Factors Is Required for Massive Liver Apoptosis Induced by Bacterial Lipopolysaccharide*
Danya Liu ,
Chunsheng Li,
Yiliu Chen,
Christie Burnett,
Xue Yan Liu,
Sheila Downs,
Robert D. Collins , and
Jacek Hawiger¶
From the
Departments of Microbiology and Immunology and Pathology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Stimulation of macrophages with lipopolysaccharide (LPS) leads to the production of cytokines that elicit massive liver apoptosis. We investigated the in vivo role of stress-responsive transcription factors (SRTFs) in this process focusing on the precipitating events that are sensitive to a cell-permeant peptide inhibitor of SRTF nuclear import (cSN50). In the absence of cSN50, mice challenged with LPS displayed very early bursts of inflammatory cytokines/chemokines, tumor necrosis factor  (1 h), interleukin 6 (2 h), interleukin 1  (2 h), and monocyte chemoattractant protein 1 (2 h). Activation of both initiator caspases 8 and 9 and effector caspase 3 was noted 4 h later when full-blown DNA fragmentation and chromatin condensation were first observed (6 h). At this time an increase of pro-apoptotic Bax gene expression was observed. It was preceded by a decrease of anti-apoptotic Bcl2 and BclXL gene transcripts. Massive apoptosis was accompanied by microvascular injury manifested by hemorrhagic necrosis and a precipitous drop in blood platelets observed at 6 h. An increase in fibrinogen/fibrin degradation products and a rise in plasminogen activator inhibitor 1 occurred between 4 and 6 h. Inhibition of SRTFs nuclear import with the cSN50 peptide abrogated all these changes and increased survival from 7 to 71%. Thus, the nuclear import of SRTFs induced by LPS is a prerequisite for activation of the genetic program that governs cytokines/chemokines production, liver apoptosis, microvascular injury, and death. These results should facilitate the rational design of drugs that protect the liver from inflammation-driven apoptosis.
Received for publication, June 28, 2004
, and in revised form, August 24, 2004.
* This work was supported in part by United States Public Health Service, National Institutes of Health Grants HL69542, HL62356, HL68744, and DK54072. The use of core facilities in this study was supported by National Institutes of Health Grants 2P30 CA 68485 (to the Vanderbilt Ingram Cancer Center) and 5P30DK058404-03 (to the Vanderbilt Digestive Disease Research 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.
¶ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Ave. South, 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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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
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