Nuclear import of proinflammatory transcription factors is required for massive liver apoptosis induced by bacterial lipopolysaccharide.
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 alpha (1 h), interleukin 6 (2 h), interleukin 1 beta (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 BclX(L) 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.
Liu
Danya
D
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Li
Chunsheng
C
Chen
Yiliu
Y
Burnett
Christie
C
Liu
Xue Yan
XY
Downs
Sheila
S
Collins
Robert D
RD
Hawiger
Jacek
J
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; C118258:SN50 peptide; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D020169:Caspases