title: Nuclear import of proinflammatory transcription factors is required for massive liver apoptosis induced by bacterial lipopolysaccharide.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Danya
authors.initials: D
authors.lastname: Liu
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Li
authors.forename: Yiliu
authors.initials: Y
authors.lastname: Chen
authors.forename: Christie
authors.initials: C
authors.lastname: Burnett
authors.forename: Xue Yan
authors.initials: XY
authors.lastname: Liu
authors.forename: Sheila
authors.initials: S
authors.lastname: Downs
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.forename: Jacek
authors.initials: J
authors.lastname: Hawiger
mesh_terms: 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
chemical_list: 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